samenvatting histo.pdf

# Nerve fibers, nerves, and the autonomic nervous system This section details the fundamental components of the nervous system, including nerve fibers, nerves, and the specialized functions of the autonomic nervous system. ### 1.1 Neurons: the functional unit of the nervous system Neurons are the smallest functional units of the nervous system. They are characterized by their ability to respond to stimuli by changing their electrical potential and to transmit this change as a nerve impulse [50](#page=50) [51](#page=51). #### 1.1.1 Neuron structure A neuron typically consists of three main parts: * **Dendrites:** These are branched extensions that receive stimuli from the environment or other neurons. They increase the surface area of the cell for stimulus reception and are rarely singular [50](#page=50) [51](#page=51) [52](#page=52). * **Perikaryon (cell body):** This is the metabolic center of the neuron, containing the nucleus and cytoplasm. It is sensitive to stimuli and houses a large, round nucleus with a prominent nucleolus and diffuse chromatin. The perikaryon also contains a highly developed rough endoplasmic reticulum (RER) responsible for Nissl substance, a Golgi apparatus, numerous mitochondria (though fewer than in terminal boutons), neurofilaments, and neurotubuli. It may also contain melanin granules, lipofuscin, and small fat droplets, but no glycogen [50](#page=50) [51](#page=51) [52](#page=52). * **Axon:** This is a long, cylindrical projection that conducts nerve impulses away from the cell body to other cells [50](#page=50) [52](#page=52). * **Axon hillock:** A short, pyramid-shaped outgrowth from which the axon originates [52](#page=52). * **Axoplasm:** The cytoplasm of the axon, which is poor in organelles [52](#page=52). * **Telodendrion:** The branched, distal end of the axon, culminating in terminal boutons (enlargements) responsible for impulse transmission [50](#page=50) [51](#page=51). * **Collaterals:** Few side branches originating from the axon [52](#page=52). * Axons contain a few mitochondria, neurofilaments, and neurotubuli but no ribosomes, meaning protein synthesis does not occur in the axon. Organelles are transported from the perikaryon [52](#page=52). #### 1.1.2 Classification of neurons Neurons can be classified based on their structure and function: * **Structural classification:** * **Multipolar:** One axon and multiple dendrites [51](#page=51). * **Bipolar:** One axon and one dendrite [51](#page=51). * **Pseudo-unipolar:** A single projection that splits into a T-shape at some distance from the cell body [51](#page=51). * **Functional classification:** * **Sensory neurons:** Receive stimuli from the environment and the body [51](#page=51). * **Motor neurons:** Influence effectors such as muscle fibers and glands [51](#page=51). * **Interneurons (Schakelneuronen):** Connect other neurons, forming complex functional chains and circuits [51](#page=51). #### 1.1.3 Synapses Synapses are functional contact points for transmitting impulses to other neurons, muscle cells, or other cells [52](#page=52). * **Types of synapses:** * **Electrical synapses:** Involve direct contact between cells through gap junctions (nexuses). They allow for bidirectional transmission of low-molecular-weight ions, such as calcium ions ($Ca^{2+}$) [53](#page=53). * **Chemical synapses:** Characterized by a physical separation between the presynaptic and postsynaptic elements, with neurotransmitters released into the synaptic cleft to bind to receptors [53](#page=53). * **Unidirectional transmission:** [53](#page=53). * **Terminal bouton:** Swollen or club-shaped ending of the presynaptic neuron [53](#page=53). * **Synaptic cleft:** The narrow space between the pre- and postsynaptic membranes [53](#page=53). * **Synaptic vesicles/vacuoles:** Contain neurotransmitters in the presynaptic terminal, converting electrical to chemical signals [53](#page=53). * **Receptors:** Located in the postsynaptic membrane, they receive the chemical signal and convert it back to an electrical signal [53](#page=53). * **Synaptic connections:** * Axodendritic (axon-dendrite) [53](#page=53). * Axosomatic (axon-cell body) [53](#page=53). * Axo-axonic (axon-axon) [53](#page=53). * Dendrosomatic (dendrite-cell body) [53](#page=53). * Dendrodendritic (dendrite-dendrite) [53](#page=53). ### 1.2 Neuroglia: supporting cells of the nervous system Neuroglia are a collection of cell types in the central nervous system (CNS) that do not directly conduct nerve impulses but provide essential support. Their functions include calcium kinetics, nutrition, and oxygen supply [53](#page=53). #### 1.2.1 Types of neuroglia * **Astrocytes (Macroglia):** Have round, central nuclei, numerous long extensions, and diffuse chromatin. They envelop blood vessels and neurons with their expanded end-feet [53](#page=53). * **Fibrous astrocytes:** Few branches, thin long processes, fibril-like structures, and indented nuclei [53](#page=53). * **Protoplasmic astrocytes:** Many branches, short processes, and few or no fibrils [53](#page=53). * **Oligodendrocytes (Macroglia):** Smaller than astrocytes with fewer and shorter extensions. They have small nuclei, numerous mitochondria, ribosomes, and microtubules, and a highly developed Golgi apparatus [54](#page=54). * In gray matter, they partially surround larger neurons [54](#page=54). * In white matter, they are arranged in rows along myelinated nerve fibers and form the myelin sheath in the CNS [54](#page=54). * **Microglia:** Possess oval nuclei, thinly branched extensions, no filaments, and poorly developed RER. They have lysosomes and originate from the mononuclear phagocyte system. Their functions include phagocytosis of invaders in the CNS and uptake of lipids during degeneration [54](#page=54). * **Ependymal cells:** Originate from the inner lining of the neural tube and are arranged epithelially. They line the cavities of the brain and spinal cord, coming into direct contact with cerebrospinal fluid. They form a cuboidal cell layer at the choroid plexus [54](#page=54) [55](#page=55). ### 1.3 Nerve fibers and nerves Nerve fibers are axons with their surrounding sheaths, while nerves are bundles of nerve fibers encased in connective tissue. #### 1.3.1 Nerve fibers * **Myelinated nerve fibers:** The axon is covered by a myelin sheath, which significantly speeds up impulse conduction [56](#page=56). * **CNS:** The myelin sheath is formed by oligodendrocytes [55](#page=55). * **PNS:** The myelin sheath is formed by Schwann cells, which wrap themselves completely around the axon. Myelin is a bimolecular lipid layer interspersed with protein molecules [55](#page=55) [56](#page=56). * **Nodes of Ranvier:** Interruptions in the myelin sheath where Schwann cells meet [56](#page=56). * **Incisure of Schmidt-Lanterman:** Cone-shaped slits within the myelin sheath, appearing as spirally wound tunnels filled with Schwann cell cytoplasm [56](#page=56). * **Unmyelinated nerve fibers:** Thin axons embedded in grooves of Schwann cells [56](#page=56). #### 1.3.2 Nerves Nerves are bundles of nerve fibers surrounded by connective tissue [56](#page=56). * **Epineurium:** The outer, fiber-rich layer of dense connective tissue [56](#page=56). * **Perineurium:** Dense connective tissue surrounding bundles of nerve fibers, containing fibroblasts and composed of collagen fibers [56](#page=56). * **Endoneurium:** A thin layer of loose connective tissue found between individual nerve fibers [56](#page=56). ### 1.4 The autonomic nervous system The autonomic nervous system (ANS) regulates automatic bodily processes unconsciously [56](#page=56). #### 1.4.1 Functions and structure * **Functions:** Regulation of smooth muscle contraction, secretion of certain glands, and control of heart rate [56](#page=56). * **Structure:** Consists of a two-neuron chain: * **First neuron (within CNS):** Its axon synapses with the second neuron in a peripheral ganglion [56](#page=56). * **Preganglionic fibers:** Nerve fibers from the first neuron to the second neuron, releasing acetylcholine as a neurotransmitter [56](#page=56). * **Postganglionic fibers:** Axons of the second neuron that innervate effectors [56](#page=56). #### 1.4.2 Divisions of the ANS * **Sympathetic nervous system:** Originates from the thoracic and lumbar regions of the spinal cord. It prepares the body for stress ('fight-or-flight') and is characterized by long preganglionic fibers and short postganglionic fibers [56](#page=56). * **Parasympathetic nervous system:** Cell bodies are located in the medulla oblongata, midbrain, and sacral spinal cord. It promotes rest and digestion ('rest-and-digest') and has long postganglionic fibers and short preganglionic fibers [57](#page=57). ### 1.5 Degeneration and regeneration of neurons Neurons, unlike most cells, cannot divide and are permanently lost if they die. However, their processes can be replaced to a limited extent, particularly in the peripheral nervous system [57](#page=57). * **Peripheral nerve fiber regeneration:** If the perikaryon remains intact, peripheral nerve fibers can regenerate. In the case of a transected axon [57](#page=57): 1. The distal segment degenerates and is removed by macrophages [57](#page=57). 2. The proximal segment, still connected to the perikaryon, begins regeneration [57](#page=57). 3. The proximal segment degenerates slightly before forming a stub [57](#page=57). 4. Schwann cells grow in a column-like fashion, guiding the regenerating axon stump [57](#page=57). 5. The proximal stump branches under increased synthetic activity from the perikaryon [57](#page=57). 6. Outgrowths that contact the Schwann cell columns continue to grow; otherwise, a bulbous swelling forms [57](#page=57). * **Changes in the perikaryon upon axonal damage:** These include chromatolysis (changes in Nissl substance), increased volume, and displacement of the nucleus to the periphery [57](#page=57). * **Transneuronal degeneration:** Neurons that are exclusively connected to a dying neuron may also die [57](#page=57). * **Neuroglia regeneration:** Neuroglia (including those in the CNS, Schwann cells, and satellite cells) can undergo mitosis and occupy the space left by lost neurons [57](#page=57). ### 1.6 Ganglia Ganglia are collections of nerve cell bodies located outside the central nervous system. They are encased in dense connective tissue and connected to nerves [57](#page=57). * **Intramural ganglia:** Located within the walls of autonomously innervated organs [57](#page=57). --- # Articular cartilage structure and function Articular cartilage is a specialized connective tissue found in synovial joints that facilitates frictionless movement and absorbs impact forces [23](#page=23). ### 2.1 Cartilage as a supporting tissue Cartilage is a flexible, water-rich, and non-brittle component of the body's supporting tissues. It is abundant in embryos and newborns, and in adults, it is found in areas requiring skeletal flexibility, such as rib joints and articulating surfaces. Crucially, cartilage lacks its own nerves, blood vessels, or lymph vessels [20](#page=20). #### 2.1.1 Types of cartilage There are three main types of cartilage: * **Hyaline cartilage:** Characterized by Type II collagen fibers and proteoglycans, forming a smooth, glassy matrix [20](#page=20). * **Elastic cartilage:** Rich in elastic fibers, providing significant flexibility and recoil [21](#page=21). * **Fibrocartilage:** Densely packed with collagen fibers, offering high resistance to compression and torsion [21](#page=21). #### 2.1.2 Histogenesis of cartilage Cartilage develops from mesenchyme. Mesenchymal cells proliferate and differentiate into chondroblasts, which then mature into chondrocytes. These cells are embedded within an extracellular matrix they synthesize. Further growth occurs through appositional (from the perichondrium) and interstitial (matrix expansion within lacunae) mechanisms [22](#page=22). ##### 2.1.2.1 Appositional growth Appositional growth involves the mitotic division of mesenchymal cells in the perichondrium, leading to an increase in cell layers and cartilage thickness [22](#page=22). ##### 2.1.2.2 Interstitial growth Interstitial growth occurs when chondroblasts and chondrocytes secrete extracellular matrix, pushing themselves further apart and forming chondrons (groups of cells resulting from incomplete cell division) [22](#page=22). ### 2.2 Hyaline cartilage Hyaline cartilage is the most common type and forms the articular cartilage found in synovial joints [20](#page=20). #### 2.2.1 Components of hyaline cartilage * **Cells:** Chondrocytes, which reside in lacunae (small cavities within the matrix). Chondrocytes are mature cells with a round shape, a prominent nucleolus, and numerous cytoplasmic extensions that increase their surface area. They possess abundant ribosomes, an extensive rough endoplasmic reticulum (RER), a well-developed Golgi apparatus, and numerous mitochondria. Chondronen, described as "pressure cushions," are also present. Chondroblasts are less mature and less active precursor cells [20](#page=20). * **Extracellular material:** * **Fibers:** Primarily composed of Type II collagen, arranged in a network [20](#page=20). * **Ground substance:** Consists of proteoglycans, to which glycosaminoglycans (GAGs) like chondroitin sulfate and keratan sulfate are attached, forming large molecules associated with hyaluronan [20](#page=20). * **Perichondrium:** The outer layer of dense connective tissue surrounding hyaline cartilage, containing progenitor cells that can differentiate into chondrocytes. It also contains blood vessels, lymph vessels, and nerve elements, although nutrition to the cartilage itself occurs via diffusion [20](#page=20). #### 2.2.2 Regeneration of hyaline cartilage Hyaline cartilage regenerates slowly due to its avascular nature. Repair primarily occurs from the perichondrium, which can grow into cartilage lesions. Calcification is a common outcome, hindering diffusion and leading to cell death [21](#page=21). ### 2.3 Elastic cartilage Elastic cartilage is characterized by a high concentration of elastic fibers, providing significant elasticity and recoil [21](#page=21). #### 2.3.1 Components of elastic cartilage * **Cells:** Chondrocytes organized within chondrons [21](#page=21). * **Extracellular material:** Abundant elastic fibers, interspersed with collagen fibers (covered by ground substance) [21](#page=21). * **Perichondrium:** Present, as in hyaline cartilage [21](#page=21). #### 2.3.2 Occurrence of elastic cartilage Elastic cartilage is found in the auricle (external ear), epiglottis, and auditory canal. Degenerative changes are rare in this type of cartilage [21](#page=21). ### 2.4 Fibrocartilage Fibrocartilage is a dense, fibrous tissue designed to withstand significant pressure and torsional forces [21](#page=21). #### 2.4.1 Components of fibrocartilage * **Cells:** Chondrocytes arranged in short rows, often forming pairs within chondrons [22](#page=22). * **Extracellular material:** Thick bundles of collagen fibers with minimal ground substance between them. It can be considered an alternating arrangement of hyaline cartilage-like matrix with chondrocytes and dense collagen fiber layers [22](#page=22). * **Perichondrium:** Absent in fibrocartilage [22](#page=22). #### 2.4.2 Occurrence of fibrocartilage Fibrocartilage is found in the intervertebral discs, at the attachment sites of some tendons, and in symphyses, articular discs, and menisci of certain joints [22](#page=22). ### 2.5 Articular cartilage structure and function Articular cartilage is a form of connective tissue found on the articulating surfaces of all synovial joints. Its primary roles are to provide a low-friction surface for joint movement and to absorb shock and compressive forces [23](#page=23). #### 2.5.1 Microscopic organization of articular cartilage Articular cartilage exhibits a zonal organization of collagen fibers relative to the bone surface [23](#page=23): * **Deep zone:** Fibers are oriented perpendicular to the bone surface. * **Middle zone:** Fibers are arranged in a random, multidirectional pattern. * **Superficial tangential zone:** Fibers run parallel to the joint surface. #### 2.5.2 Cellular component of articular cartilage * **Cells:** Chondrocytes constitute 10% or less of articular cartilage. They have limited contact with each other and their numbers decrease with age. Chondroblasts, the precursor cells, are rounder, larger, and possess a more developed ER than chondrocytes. Chondrocytes are more elongated with a less developed ER and fewer mitochondria compared to chondroblasts [23](#page=23). #### 2.5.3 Matrix of articular cartilage The matrix is the extracellular component and is divided into pericellular, territorial, and interterritorial regions. It consists of [24](#page=24): * **Water:** A significant component, crucial for its mechanical properties [24](#page=24). * **Collagen fibers:** Primarily Type II collagen, forming a meshwork that supports proteoglycans and glycosaminoglycans [24](#page=24). * **Non-collagenous fibers:** Contribute to stability and are formed into proteoglycan aggregates. These include net-forming proteins and linking proteins that bind cells to proteoglycan aggregates and collagen fibrils [24](#page=24). * **Proteoglycans and glycosaminoglycans (GAGs):** Hyaluronic acid forms a central chain to which proteoglycans bind. Each proteoglycan has a central protein chain attached to GAGs, which are highly negatively charged and can bind water, sodium ions ($Na^+$), and calcium ions ($Ca^{2+}$). Multiple proteoglycans attached to a hyaluronic acid chain form proteoglycan aggregates [24](#page=24). #### 2.5.4 Water homeostasis in articular cartilage The regulation of water content is vital for articular cartilage function [25](#page=25). * **Synthetic activity:** Cartilage cell synthesis activity, influenced by physiological loads, regulates water homeostasis. This activity is high during growth phases and involves a balance between the synthesis of extracellular components and physiological degradation [25](#page=25). * **Nutrient supply:** Macromolecule synthesis requires oxygen, amino acids, and glucose, supplied via diffusion from synovial fluid. The joint capsule regulates the quality and quantity of this supply, impacting regenerative capacity [25](#page=25). * **Piezo-electric effect:** Alternating loading stimulates oxygen and nutrient transport, generating electrical potential fluctuations that stimulate matrix synthesis by chondrocytes [25](#page=25). * **Loading and unloading:** The transport of water is pressure-dependent. Under pressure, water moves from high to low pressure areas, and the cartilage returns to its original shape upon unloading, a phenomenon known as visco-elasticity. Water can infiltrate the subchondral bone or synovial fluid under load and returns during unloading [25](#page=25). #### 2.5.5 Mechanical forces acting on articular cartilage Articular cartilage experiences several types of mechanical forces: * **Creep:** A deformation that occurs over time due to the rearrangement of collagen networks and fibrils, influenced by water movement. This is maximal when compression, binding, and repulsive forces from GAGs are balanced. Damage to collagen fibrils can occur if the load exceeds the cartilage's capacity [25](#page=25) [26](#page=26). * **Stress-relaxation:** Occurs as water moves through the cartilage during compression until equilibrium is reached. This involves intrinsic visco-elastic properties related to fluid redistribution within the cartilage [26](#page=26). #### 2.5.6 Factors affecting articular cartilage function Mechanical deformation of chondrocytes influences their synthesis activity. Physiological mechanisms can be disrupted by [26](#page=26): * Chronic inflammation of the joint capsule [26](#page=26). * Intra-articular bleeding [26](#page=26). * Certain medications [26](#page=26). * Specific dietary components, such as pork [26](#page=26). * Joint-damaging substances [26](#page=26). * Imbalanced loading and unloading, leading to disturbed force equilibrium that regulates water transport [26](#page=26). ### 2.6 Degeneration and osteoarthritis Osteoarthritis is characterized by the degeneration of articular cartilage [26](#page=26). #### 2.6.1 Causes of osteoarthritis * **Reduced alternation between loading and unloading:** This is a significant factor [26](#page=26). * **Age-related degeneration:** The synthesis activity declines with age, leading to shorter hyaluronic acid and chondroitin sulfate chains and altered ground substance production. Immobilization also contributes to this process [26](#page=26). --- # Water regulation and mechanical properties of articular cartilage This section details how articular cartilage maintains its water content and how mechanical forces influence its structure and function, impacting its susceptibility to degeneration. ### 3.1 Regulation of water balance The water balance within articular cartilage is a dynamic process influenced by cellular synthesis, nutrient supply, and mechanical loading [25](#page=25). #### 3.1.1 Synthesis activity Cartilage cells actively synthesize extracellular matrix components, which plays a crucial role in regulating water content. This synthesis is particularly high during youth and the growth phase, maintaining a balance between the formation of new extracellular constituents and physiological degradation. Proteoglycans and glycosaminoglycans (GAGs) are continuously and rapidly renewed [25](#page=25). #### 3.1.2 Nutrient supply The synthesis of macromolecules within cartilage necessitates oxygen, amino acids, and glucose. These nutrients are supplied to the cells via diffusion from the synovial fluid, with the joint capsule regulating the quality and quantity of this supply. The quality of the synovial fluid has a significant impact on cartilage health and regeneration capabilities [25](#page=25). #### 3.1.3 Piezo-electric effect Alternating mechanical loading stimulates the transport of oxygen and nutrients through articular cartilage by inducing fluctuations in the tissue's electrical potential. This piezo-electric activity provides a stimulus for chondrocytes to synthesize matrix, leading to tissue organization [25](#page=25). #### 3.1.4 Loading and unloading Water transport within articular cartilage is dependent on pressure loading. Under pressure, the shape of the cartilage changes, causing water to move from high-pressure to low-pressure areas. During unloading, the matrix can rehydrate, a phenomenon known as visco-elasticity. Water can also infiltrate the synovial fluid and subchondral bone under load, returning to the cartilage upon unloading. The amount of water that can be expelled from the cartilage is limited by the compression force, deformation force, and binding forces [25](#page=25). > **Tip:** The visco-elastic nature of cartilage is crucial for its ability to withstand and dissipate loads, involving the movement of water within the tissue. ### 3.2 Mechanical properties of articular cartilage Articular cartilage exhibits specific mechanical behaviors under load, primarily related to its fluid content and structural components. #### 3.2.1 Biphasic creep behavior Creep is a deformation that occurs under sustained load, attributed to the deformation of the collagen network and fibrils. In a resting state, collagen fibrils are at a certain distance and attract water and ions. The extent of creep is dependent on how much water can leave the cartilage, reaching a maximum when compression force, binding force, and the repulsive force of GAGs are in equilibrium. Exceeding the cartilage's load-bearing limit can lead to damage of the collagen fibrils [25](#page=25) [26](#page=26). #### 3.2.2 Biphasic stress-relaxation Stress-relaxation occurs as water moves through the cartilage during compression, exiting into the synovial fluid and subchondral bone until an equilibrium in pressure is reached. This is an intrinsic visco-elastic property not dependent on external factors. It involves the redistribution of fluid within the cartilage to achieve an equilibrium state [26](#page=26). > **Example:** During activities like walking, the initial impact causes water to be squeezed out of the cartilage (stress). As the joint remains under load for a period, the fluid redistribution and the matrix's intrinsic properties lead to a reduction in internal stress (relaxation). #### 3.2.3 Influence of mechanical deformation on synthesis Mechanical deformation of chondrocytes directly influences their synthesis activity [26](#page=26). #### 3.2.4 Disruption of physiological mechanisms Several factors can disrupt these physiological mechanisms: * Chronic inflammation of the joint capsule [26](#page=26). * Bleeding within the joint [26](#page=26). * Certain medications [26](#page=26). * Specific dietary components, such as pork [26](#page=26). * Joint-damaging substances, even under normal loading [26](#page=26). * Loading typically moves waste products to the subchondral bone and synovial fluid, while unloading facilitates nutrient and oxygen transport to the cells [26](#page=26). * Continuous unloading or unilateral compression disrupts the force balance that regulates water transport [26](#page=26). ### 3.3 Degeneration and arthrosis (osteoarthritis) Degeneration and arthrosis arise from imbalances in loading and other factors that compromise cartilage integrity. #### 3.3.1 Causes of degeneration * **Reduced alternation between loading and unloading:** * **Age-related degeneration:** Occurs with increasing age, characterized by decreased synthesis activity, shortening of hyaluronic acid and chondroitin sulfate chains, and changes in ground substance production. Immobilization also leads to a lack of positive physiological stimuli [26](#page=26) [27](#page=27). * **Underloading:** Lack of loading or unilateral loading patterns, common in sedentary occupations, leads to insufficient nutrition for chondrocytes and reduced stimulation for chondroblasts. This results in less matrix production, impaired fluid transport, reduced ground substance, less water binding, decreased collagen network tension, and increased deformability [27](#page=27). * **Overloading:** Excessive body weight or continuous unilateral loading leads to wear that exceeds the cells' capacity to repair. This can cause increased water binding due to collagen damage, leading to greater tension and cartilage being pushed away, potentially entering the synovial fluid and triggering inflammation. This can lead to osteoarthrosis [27](#page=27). > **Note:** During loading, cartilage structure compresses, bringing negative charges closer, which expels water and ions into the synovial space. Under normal circumstances, wear is replaced by chondroblasts and chondrocytes to replenish the extracellular matrix [27](#page=27). * **Increasing ossification of articular cartilage:** * **Shifting tidemark:** The boundary between cartilage and bone moves towards the cartilage surface, increasing the mineralized cartilage zone and initiating ossification. The softer cartilage thins, increasing deformation under load, leading to quicker attainment and overstepping of the load limit and subsequent damage to the collagen network. This also impairs diffusion and osmosis between the subchondral bone and cartilage, reducing matrix synthesis [27](#page=27) [28](#page=28). * **Rising pH:** Increased vascularization and innervation in the subchondral bone lead to their penetration into the calcified cartilage zone, increasing the pH. A higher pH favors osteoblasts and osteocytes, promoting mineral-rich matrix production, while creating an unfavorable environment for chondroblasts and chondrocytes [28](#page=28). * **Trauma:** Injuries from sports or daily life can cause large cartilage fragments to break off, becoming "joint mice" within the joint capsule and potentially leading to premature arthrosis [28](#page=28). ### 3.4 Regeneration of articular cartilage Regeneration of articular cartilage is a very slow process. Passive joint movements serve as a stimulus for regeneration. Damage to the subchondral bone can influence this process, and cells may synthesize larger amounts of extracellular matrix. Exercises with low load in the affected area are also recommended [28](#page=28). ### 3.5 Lubrication of the joints Joint lubrication is essential for minimizing friction during movement, such as walking or running [28](#page=28). #### 3.5.1 Boundary lubrication This occurs via a thin layer of glycoproteins or lubrication proteins that adhere to the cartilage surface, preventing direct contact between the articular surfaces [28](#page=28). #### 3.5.2 Lubrication by a fluid film * **Squeeze film lubrication:** This involves the entrapment and compression of fluid between the articulating surfaces [28](#page=28). * **Hydrodynamic lubrication:** This type of lubrication, particularly evident in rolling movements, avoids direct contact between cartilage surfaces. A small amount of water is retained during loading, acting like a ball bearing [28](#page=28). --- # Bone tissue: structure and composition Bone tissue is a specialized connective tissue that forms the skeletal framework of the body, characterized by its rich inorganic crystal content, presence of blood vessels and nerves, and its dynamic, metabolically active nature undergoing constant remodeling [30](#page=30). ### 4.1 Macroscopic and microscopic subdivisions Bone tissue can be broadly categorized macroscopically into two types: compact bone, which is dense and solid, and spongy bone, which consists of a network of trabeculae and intervening spaces containing blood-forming cells (bone marrow). Microscopically, bone is classified as lamellar bone (secondary bone) and pexiform bone (primary bone), with pexiform bone being rapidly replaced by lamellar bone [30](#page=30). #### 4.1.1 Lamellar bone Lamellar bone is the mature form of bone tissue. In compact bone, lamellar bone is organized into osteons, also known as Haversian systems. These osteons comprise [30](#page=30): * Cylindrical lamellae concentrically arranged around a Haversian canal [30](#page=30). * Haversian canals, which contain blood vessels and nerves and connect to other canals or the bone marrow [30](#page=30). * Volkmann's canals, which are transverse connections between Haversian canals [30](#page=30). * Interstitial lamellae, filling the spaces between osteons [30](#page=30). * Circumferential lamellae that encircle the entire structure of osteons, covered by the periosteum, a connective tissue sheath [30](#page=30). * Endosteum, a connective tissue layer lining the inner cavities of the bone [30](#page=30). Lamellar bone also includes non-organized components, such as cell processes connected by gap junctions [30](#page=30). #### 4.1.2 Pexiform bone Pexiform bone is an immature and highly compact form of bone tissue. In pexiform bone, osteocytes are uniformly distributed within the matrix, and there is no specific orientation of collagen fibers, which run in various directions [30](#page=30). ### 4.2 Components of bone tissue The composition of bone tissue includes cellular elements and extracellular material [31](#page=31). #### 4.2.1 Bone cells There are three main types of bone cells: osteoblasts, osteocytes, and osteoclasts [31](#page=31). ##### 4.2.1.1 Osteoblasts Osteoblasts are young, active bone-forming cells derived from osteoprogenitor cells of mesenchymal origin. They are essential for bone formation and are found where bone matrix is being synthesized. Their functions include [31](#page=31): * Producing fibers, specifically type I collagen [31](#page=31). * Playing a role in ossification (osteogenesis) [31](#page=31). Osteoblasts have a varied shape and an epithelioid arrangement, with a large nucleus containing a single peripheral nucleolus. Their cytoplasm is rich in RNA and contains well-developed rough endoplasmic reticulum (RER), Golgi apparatus, and mitochondria, facilitating the production of tropocollagen I and glycosaminoglycans, and releasing alkaline phosphatase crucial for ossification. As they synthesize more osteoid (bone matrix), osteoblasts can differentiate into flattened cells with cellular extensions, maintaining contact with each other via gap junctions. They also contain small granules known as calcoferites, spherulites, or matrix granules, which act as crystallization centers during calcification [31](#page=31). ##### 4.2.1.2 Mineralization process Mineralization is the process by which osteoblasts form bone tissue. It involves the deposition of needle-shaped hydroxyapatite crystals onto collagen fibrils within the ground substance at regular intervals. Key aspects of mineralization include [31](#page=31): * The role of alkaline phosphatase, which increases the local concentration of calcium ions ($Ca^{2+}$) and phosphate ions ($PO_4^{—}$), accelerating the process [32](#page=32). * Osteoblasts becoming embedded within the bone matrix, which can impede diffusion, necessitating the use of gap junctions (nexus) for cell communication [32](#page=32). * The formation of a calcification-free zone around the bone cell, containing only osteoid and microfibrils, where osteoblasts, now termed osteocytes, remain in contact via canaliculi. Canaliculi are small channels housing cell extensions that provide nutrients to the cells [32](#page=32). ##### 4.2.1.3 Osteocytes Osteocytes are mature bone cells embedded within the mineralized extracellular matrix. In lamellar bone, they are arranged in parallel rows and communicate with neighboring cells via gap junctions. Osteocytes have a denser-staining nucleus and cytoplasm containing fat and glycogen, and they are responsible for maintaining the extracellular matrix [32](#page=32). ##### 4.2.1.4 Osteoclasts Osteoclasts are highly active bone cells originating from the mononuclear phagocyte system in the bone marrow. Their primary function is to break down bone matrix. This process involves [32](#page=32): 1. Pumping numerous protons ($H^+$) outward, creating a highly acidic environment beneath the osteoclast [32](#page=32). 2. Dissolving calcium carbonates and calcium phosphates [32](#page=32). 3. Phagocytosing hydroxyapatite crystals and degrading them within phagolysosomes [32](#page=32). This bone resorption is crucial for bone modeling, which requires the coordinated action of osteoblasts and osteoclasts, and is influenced by mechanical pressure. Osteoclasts possess multiple nuclei, chromatin-rich nuclei, and distinct nucleoli. Their cytoplasm contains well-developed RER, Golgi apparatus, numerous mitochondria (due to high energy demands), and abundant lysosomes, which are used to excavate tunnels by lysing mineralized bone, forming Howship's lacunae. The cell membrane of osteoclasts features a ruffled membrane with numerous folds resembling microvilli, and they move via amoeboid motion [32](#page=32). **Tip:** Bone remodeling is a continuous process involving both bone formation by osteoblasts and bone resorption by osteoclasts, a dynamic balance influenced by hormonal and mechanical factors. Stimulation of osteoclast activity is promoted by parathyroid hormone (PTH) from the parathyroid gland, while calcitonin from the thyroid gland inhibits it. Osteoclasts play a vital role in regulating blood calcium concentration. If blood calcium levels are too low, osteoclasts are stimulated to release calcium from bone into the bloodstream. Conversely, if blood calcium levels are too high, calcium is deposited into the bone structure, and osteoclast activity is inhibited [33](#page=33). #### 4.2.2 Extracellular material The extracellular material of bone is a composite of collagen fibers and ground substance [33](#page=33). ##### 4.2.2.1 Collagen fibers These are primarily type I collagen fibers that are encrusted with hydroxyapatite crystals. Calcium salts constitute approximately 65% of the weight of the extracellular material [33](#page=33). ##### 4.2.2.2 Ground substance The ground substance of bone consists of proteoglycans, which contain less sulfur compared to those in cartilage. It is not basophilic and not metachromatic [33](#page=33). ### 4.3 Bone formation Bone formation, or ossification, is the process of creating new bone tissue. There are two primary types of ossification: direct (desmal) bone formation and indirect (chondral) bone formation [33](#page=33). #### 4.3.1 Direct (desmal) bone formation This process occurs without the involvement of cartilage. Examples include the formation of the skull bones. The steps are [33](#page=33): 1. Mesenchymal cells condense in specific, genetically determined areas [33](#page=33). 2. These mesenchymal cells become spindle-shaped and begin producing tropocollagen and proteoglycans, forming the extracellular matrix (osteoïd). At this stage, they are considered osteoblasts [33](#page=33). 3. Osteoblasts then produce alkaline phosphatases and matrix granules, leading to the deposition of calcium salts onto collagen fibrils and the calcification of the osteoid. The osteoblast is now considered an osteocyte [33](#page=33). #### 4.3.2 Indirect (chondral) bone formation This type of bone formation involves cartilage as an intermediate structure, as seen in the formation of long bones like the femur. (Further details on chondral ossification are not provided in the given text.) [33](#page=33). --- # Bone formation and joint structure This topic delves into the intricate processes of bone formation and the structural organization of joints within the skeletal system. ### 5.1 Bone formation Bone formation, also known as ossification, involves the creation of new bone tissue through two primary mechanisms: direct (desmal) and indirect (chondral) ossification [33](#page=33). #### 5.1.1 General principles of bone matrix The extracellular matrix of bone is composed of collagen fibers, primarily type I, which are encrusted with hydroxyapatite crystals. These calcium salts constitute approximately 65% of the extracellular material's weight. The ground substance comprises proteoglycans, which are less sulfurous than those found in cartilage, are not basophilic, and are not metachromatic [33](#page=33). Regulation of blood calcium concentration plays a crucial role in bone metabolism. When calcium levels are too low, the body extracts calcium from the diet or bone structure, stimulating osteoclasts to release calcium into the blood. Conversely, when calcium levels are too high, calcium is deposited in the bone structure, and osteoclast activity is inhibited [33](#page=33). #### 5.1.2 Direct (desmal) bone formation Direct ossification occurs when mesenchymal tissue is directly transformed into bone, without the involvement of cartilage. This process is characteristic of bones like the skull [33](#page=33). The steps involved are: 1. Mesenchymal cells condense in genetically predetermined areas [33](#page=33). 2. These cells become spindle-shaped, producing tropocollagen and proteoglycans to form the extracellular matrix, known as osteoid. The mesenchymal cells differentiate into osteoblasts [33](#page=33). 3. Osteoblasts secrete alkaline phosphatases and matrix granules, leading to the deposition of calcium salts on collagen fibrils and the calcification of osteoid, forming bone matrix. Osteoblasts embedded in the matrix become osteocytes. Calcification zones develop into plexiform bone [33](#page=33) [34](#page=34). 4. Osteoblasts arrange epithelioidly around bone centers, forming new osteoid layers that calcify, resulting in layered bone spicules that fuse to create a meshwork of desmal bone [34](#page=34). Abundant capillaries surround ossification centers. Osteoclasts later shape the bone by resorbing portions of the desmal bone. The skull, for example, is formed from multiple bone plates connected by connective tissue [34](#page=34). > **Tip:** Desmal bone formation is an important process for flat bones and the skull. #### 5.1.3 Indirect (chondral) bone formation Indirect ossification involves the formation of bone through a cartilage intermediate, typically seen in long bones. This process begins in the seventh embryonic week [34](#page=34). Chondral bone formation can be divided into two processes: perichondral and endochondral ossification. ##### 5.1.3.1 Perichondral bone formation This process is analogous to desmal bone formation, occurring within the perichondrium surrounding the cartilage model [34](#page=34). 1. The perichondrium expands circumferentially from the midpoint of the diaphysis towards the epiphyses, forming a bone collar that strengthens the shaft and reduces nutrient diffusion to the underlying cartilage [34](#page=34). 2. Mesenchymal cells in the innermost layer of the perichondrium differentiate into osteocytes, and the perichondrium becomes the periosteum [34](#page=34). ##### 5.1.3.2 Endochondral bone formation This is the process where cartilage is replaced by bone, starting in the diaphysis [34](#page=34). 1. Central chondrocytes in the diaphysis hypertrophy due to the constricting bone collar and secrete matrix granules or spherules, leading to calcification of the cartilage matrix. This calcification impedes nutrient diffusion, causing further hypertrophy and cell death, and this process extends towards the epiphyses [34](#page=34). 2. In areas where calcification has not yet begun, cartilage cells divide and proliferate, forming parallel columns of stacked chondrocytes towards the epiphyses. This zone is known as the growth plate zone, and it is responsible for longitudinal bone growth. The bone collar prevents the radial expansion of the diaphyseal cartilage [34](#page=34). 3. A bud of connective tissue and blood vessels, termed the osteogenic bud, penetrates the bone collar centrally. This bud arises from mesenchymal cells differentiating into chondroclasts (similar to osteoclasts) that create an opening in the bone collar. Mesenchymal cells, chondroblasts, and a blood vessel loop then enter [34](#page=34) [35](#page=35). 4. The invading mesenchymal cells differentiate into bone-forming and blood-forming cells. Chondroclasts break down calcified cartilage and invade lacunae of degenerated chondrocytes, forming irregular spaces within the diaphysis known as the primary marrow cavity [35](#page=35). 5. The ingrowing blood vessels branch and extend towards both epiphyses, leaving remnants of calcified cartilage as vertical spicules. The opening through which the osteogenic bud enters is called the nutrient foramen [35](#page=35). 6. Some invading mesenchymal cells differentiate into osteoblasts, which deposit osteoid onto the calcified cartilage remnants [35](#page=35). **Bone formation in the epiphysis:** 1. Centrally located chondrocytes hypertrophy and degenerate [35](#page=35). 2. The matrix calcifies [35](#page=35). 3. An osteogenic bud invades the area [35](#page=35). 4. Osteoblasts are deposited on the calcified cartilage remnants of the epiphysis [35](#page=35). 5. The epiphyseal marrow cavity expands towards the diaphysis [35](#page=35). 6. Fusion of the epiphyseal and diaphyseal marrow cavities occurs, marking the cessation of longitudinal growth [35](#page=35). > **Note:** Cartilage in the epiphyseal heads, which form articular surfaces, does not ossify. This retained cartilage provides resilient cushioning and is composed of type II collagen [35](#page=35). #### 5.1.4 Permanent metabolic adjustments after bone formation After initial bone formation, continuous remodeling occurs throughout life: * The marrow cavity enlarges with age due to resorption by osteoclasts on the inner surface [35](#page=35). * Bone diameter increases [35](#page=35). * Concentric lamellae form around blood vessels within the marrow space, creating the characteristic osteon structure [35](#page=35). * This remodeling process continues throughout life [35](#page=35). #### 5.1.5 Bone regeneration Bone regeneration, or fracture healing, depends on how well the broken ends align. * **If fracture ends align well:** 1. Young cells from the periosteum, endosteum, and reticulum cells (from bone marrow) proliferate [36](#page=36). 2. These cells migrate into the fracture hematoma [36](#page=36). 3. A connective tissue bridge, the fibrous callus, forms [36](#page=36). 4. Osteoid develops within this tissue [36](#page=36). 5. The osteoid calcifies, forming plexiform bone [36](#page=36). * **If fracture ends do not align well:** 1. Young cells from the periosteum, endosteum, and reticulum cells proliferate [36](#page=36). 2. Cells migrate into the fracture hematoma [36](#page=36). 3. A connective tissue bridge, the fibrous callus, forms [36](#page=36). 4. Cartilage forms within the fibrous callus [36](#page=36). 5. The cartilage is replaced by endochondral bone [36](#page=36). 6. The callus is remodeled [36](#page=36). ### 5.2 Joint structure Joints are anatomical sites where two or more skeletal elements make temporary or permanent contact [36](#page=36). #### 5.2.1 Types of joints Joints can be classified based on their duration of contact or their structural composition. * **Temporary joints:** These include cartilaginous growth plates that connect epiphyses to the bone shaft and disappear at skeletal maturity [36](#page=36). * **Permanent joints:** These are further categorized into fibrous, cartilaginous, and synovial joints [36](#page=36). #### 5.2.2 Fibrous joints These joints are held together by dense connective tissue. * **Sutures:** These are firm connections found between skull bones, allowing for slight deformation (synarthroses) [36](#page=36). * **Syndesmoses:** These are fibrous joints that permit partial movement due to a greater amount of fibrous tissue between the bone segments, such as between the radius and ulna [36](#page=36). #### 5.2.3 Cartilaginous joints In these joints, the connecting surface of the bone is covered with cartilage. * Cartilage in one bone is connected to another bone, as seen in the sternocostal joint of the first rib and the pubic symphysis [37](#page=37). #### 5.2.4 Synovial joints Synovial joints are characterized by the connection of two bones via a joint capsule. * **Joint capsule:** * The outer layer consists of dense collagenous connective tissue that merges with the periosteum of the adjacent bone [37](#page=37). * The inner layer is composed of one to two layers of synovial cells, which are small, flattened fibroblasts and macrophages. This layer lacks a basal lamina and forms folds called bursae. It produces synovial fluid [37](#page=37). * **Synovial membrane:** This membrane produces synovial fluid [37](#page=37). * **Joint space:** This is the cavity between the articulating bones [37](#page=37). * **Synovial fluid:** Located within the joint space, it functions as a lubricant and provides nutrients to the hyaline cartilage. It is a dialysate of blood, enriched with hyaluronic acid and proteins [37](#page=37). * **Hyaline cartilage:** Covers the bone ends within the joint [37](#page=37). * **Ligaments:** These are strong connective tissues that stabilize the joint [37](#page=37). --- # Structure and function of extracellular matrix fibers The extracellular matrix (ECM) is a complex network of molecules that provides structural support, mechanical strength, and biochemical cues to cells and tissues. Its fibrous components, primarily collagen and elastin, play crucial roles in determining the physical properties and functions of connective tissues [10](#page=10). ### 6.1 Components of connective tissue Connective tissue is composed of cells and the extracellular matrix (ECM). The ECM itself consists of three main components: fibers, ground substance, and tissue fluid [10](#page=10). ### 6.2 Fibers Fibers are thin filaments with limited length found within the ECM, providing structural integrity and mechanical resistance. The primary types of fibers are collagen and elastic fibers [10](#page=10). #### 6.2.1 Collagen fibers Collagen fibers are the most abundant protein in mammals and are characterized by their high tensile strength and inextensibility [10](#page=10). * **Structure:** Collagen is built from tropocollagen molecules, which are linked head-to-tail and laterally to form fibrils. These fibrils are often wavy, contributing to the elasticity of tissues like skin [10](#page=10). * **Types of Collagen:** * **Type I:** * **Function:** High tensile strength [10](#page=10). * **Glycosaminoglycan Interaction:** Minimal interaction, primarily with dermatan sulfate [10](#page=10). * **Synthesis:** Produced by fibroblasts, osteoblasts, chondroblasts, and odontoblasts [10](#page=10). * **EM Image:** Densely packed, thick fibrils with variable cross-sections [10](#page=10). * **Location:** Dermis, bone, tendons, organ capsules, fibrous cartilage [10](#page=10). * **Type II:** * **Function:** Resistance to intermittent pressure [10](#page=10). * **Glycosaminoglycan Interaction:** High interaction, primarily with chondroitin sulfate [10](#page=10). * **Synthesis:** Produced by chondroblasts [10](#page=10). * **EM Image:** Very thin fibrils within an abundant ground substance, with no visible fibers [10](#page=10). * **Location:** Hyaline and elastic cartilage [10](#page=10). * **Type III:** * **Function:** Maintains structure in organs that change shape [11](#page=11). * **Glycosaminoglycan Interaction:** Moderate interaction, primarily with heparan sulfate [11](#page=11). * **Synthesis:** Produced by smooth muscle cells, fibroblasts, reticulum cells, Schwann cells, and hepatocytes [11](#page=11). * **EM Image:** Loosely aggregated thin fibrils of uniform diameter [11](#page=11). * **Location:** Smooth muscle, arteries, liver, spleen, kidneys, lungs, endoneurium [11](#page=11). * **Type IV:** * **Function:** Support, adhesion, and filtration [11](#page=11). * **Glycosaminoglycan Interaction:** Insufficient data [11](#page=11). * **Synthesis:** Produced by epithelial cells (endothelial cells) [11](#page=11). * **EM Image:** No visible fibrils [11](#page=11). * **Location:** Basal laminae of epithelia and endothelia [11](#page=11). * **Type V:** * **Function:** Insufficient data [11](#page=11). * **Glycosaminoglycan Interaction:** Insufficient data [11](#page=11). * **Synthesis:** Insufficient data [11](#page=11). * **EM Image:** Insufficient data [11](#page=11). * **Location:** Basal laminae of the placenta and some blood vessels [11](#page=11). * **Reticular fibers:** These are a special, thinner form of collagen fibers, primarily composed of collagen type III, glycoproteins, and proteoglycans. They provide support to cells, for example, in the bone marrow during blood formation [11](#page=11). #### 6.2.2 Elastin Elastin is a globular protein that polymerizes to form elastic fibers, imparting elasticity to tissues [11](#page=11). * **Structure:** Elastic fibers form networks that can fuse at junctions, often due to an increase in amorphous material. They are thinner and run more tightly than collagen fibers, forming a network where they fuse at intersections. They lack a transverse banding pattern. The structure consists of an amorphous central mass of elastin surrounded by a sheath of tubular microfibrils [11](#page=11) [12](#page=12). * **Properties:** Although elastic networks often lie among abundant collagen fibers, they allow for deformation. Collagen fiber bundles have a wavy course, only becoming taut after some expansion [12](#page=12). * **Contribution to Tissue:** Up to 50% of connective tissue can be elastic [12](#page=12). * **Examples:** Fenestrated membranes in blood vessels are examples of structures rich in elastic components [11](#page=11). ### 6.3 Ground substance The ground substance is a gel-like material in which the fibers are embedded within the ECM. It is colorless, transparent, homogeneous, and viscous, which helps prevent the entry of foreign particles [12](#page=12). * **Components:** * **Glycosaminoglycans (GAGs):** These are linear polysaccharides formed from long chains of disaccharides [12](#page=12). * **Disaccharide units:** Composed of uronic acid and hexosamine [12](#page=12). * **Protein linkage:** Covalently bound to a protein core (except for hyaluronic acid) [12](#page=12). * **Hydrophilicity:** Contain hydroxyl, carboxyl, and sulfate groups, making them strongly hydrophilic and behave as polyanions. They bind to many Na+ ions [12](#page=12). * **Major Proteoglycans:** Bound to dermatan sulfate, chondroitin sulfate, or heparan sulfate [12](#page=12). * **Synthesis:** The protein component is made in the RER, glycosylation begins in the RER and is completed in the Golgi apparatus, and sulfation occurs in the Golgi apparatus [12](#page=12). * **Degradation:** Broken down by lysosomal enzymes in various cell types. They have a high replacement rate [12](#page=12). * **Key GAGs:** Hyaluronic acid (cartilage, umbilical cord), dermatan sulfate (organ capsules, collagenous structures), chondroitin 4- or 6-sulfate (hyaline and elastic cartilage), and heparan sulfate (structures with abundant reticular fibers) [12](#page=12). * **Structural Glycoproteins:** These are proteins containing carbohydrates, with the protein component dominating [12](#page=12). * **Carbohydrate structure:** Contain non-linear polysaccharide chains of disaccharides, always including glycosamine, with a branched structure [12](#page=12). * **Key Glycoproteins:** * **Fibronectin:** Involved in the adhesion of connective tissue cells and ECM material [13](#page=13). * **Laminin:** Involved in the adhesion of epithelium to the basal lamina [13](#page=13). ### 6.4 Tissue fluid Tissue fluid is the fluid found in the interstitial spaces of tissues, serving a transport function [13](#page=13). * **Function:** Transports waste products from cells to the bloodstream for excretion or detoxification, and oxygen from the bloodstream to cells [13](#page=13). * **Quantity:** Present in small amounts [13](#page=13). * **Composition:** Contains ions, soluble substances (similar to blood plasma), and low-molecular-weight proteins [13](#page=13). * **Formation:** Arises from the interplay of two pressures in blood vessels: * **Hydrostatic pressure:** The pressure exerted by blood flow on the vessel wall, pushing water and ions out of the vessel [13](#page=13). * **Colloid-osmotic pressure:** The osmotic pressure created by proteins in the blood plasma that cannot cross the vessel wall, drawing water and ions back into the vessel [13](#page=13). * **Net effect:** These two pressures largely compensate each other, although tissue also exerts similar pressures [13](#page=13). > **Tip:** The balance between hydrostatic and colloid-osmotic pressures in capillaries is crucial for maintaining tissue fluid homeostasis and preventing edema. ### 6.5 Cells involved in ECM production and maintenance While the focus is on fibers, several cells are integral to their synthesis, maintenance, and remodeling. * **Fibroblasts:** The most common connective tissue cells, responsible for synthesizing fibrous material and amorphous ground substance. Active fibroblasts are characterized by numerous cytoplasmic extensions, an oval nucleus with fine chromatin, a large nucleolus, abundant RER, and a well-developed Golgi apparatus. Fibrocytes are the quiescent, smaller form with fewer extensions and a more condensed nucleus. Fibroblasts divide rarely but are important for wound healing. Myofibroblasts, which develop during wound healing, possess contractile properties [13](#page=13) [14](#page=14). * **Mast cells:** Play a role in immune responses, particularly allergic reactions and defense against parasitic infections. They contain granules with histamine, ECF-A, heparine, and SRS-A [14](#page=14). * **Plasma cells:** Mature B-lymphocytes that produce antibodies. They have a highly developed RER and a characteristic nucleus with heterochromatin condensations resembling spokes of a wheel [15](#page=15). * **Macrophages:** Immune cells involved in phagocytosis, digestion of particles, and the activation of other immune cells. They are highly motile and long-lived, originating from precursor cells in the bone marrow [15](#page=15). * **Leukocytes:** White blood cells originating from the blood, migrating into connective tissue, especially during inflammation. Different types, including eosinophils, basophils, and lymphocytes (T and B cells), have distinct functions in immunity [15](#page=15) [16](#page=16). * **Chromatophores:** Pigmented cells found in connective tissue, such as melanophores in humans, which absorb light [16](#page=16). --- # Spiermusculatuur: structuur, contractie en innervatie Muscle tissue is composed of cells capable of contraction [41](#page=41). ### 6.1 Types of muscle tissue There are three main types of muscle tissue: skeletal muscle, cardiac muscle, and smooth muscle [41](#page=41). ### 6.2 Skeletal muscle tissue Skeletal muscle is attached between two parts of the skeleton and is responsible for voluntary movement [41](#page=41). #### 6.2.1 Macroscopic and microscopic structure Skeletal muscle cells originate from mononucleated myoblasts that fuse to form syncytia. These mature muscle cells are very long and are called muscle fibers. Macroscopically, muscles are composed of muscle fibers, which are bundled together. A thin connective tissue sheath called endomysium surrounds each muscle fiber, while a thicker layer, the perimysium, encloses bundles of muscle fibers, and the epimysium forms a strong sheath around the entire muscle [41](#page=41). Light microscopy reveals parallel, long, multinucleated cells with peripherally located nuclei beneath the sarcolemma (the muscle fiber's cell membrane). The cytoplasm of a muscle fiber is called sarcoplasm. Within the sarcoplasm, myofibrils are visible in the longitudinal direction, which are the contractile elements of the muscle fiber. These myofibrils are composed of actin and myosin filaments. In the transverse direction, A-bands, I-bands, and Z-lines are observable [41](#page=41) [42](#page=42). Electron microscopy shows contractile proteins and a triad structure. Other elements include intermyofibrillar mitochondria (sarcosomes) for energy supply during contraction, glycogen particles, subsarcolemmal mitochondria for substrate uptake and energy production, and a small amount of RER and ribosomes. The distance between fats, glycogen, and mitochondria depends on fitness levels [42](#page=42). #### 6.2.2 Myofibrils: contractile elements Myofibrils are the contractile units of muscle fibers [42](#page=42). * **Actin filaments:** These are the main component of the I-band and consist of two helically wound chains of globular actin molecules, a tropomyosin thread made of two polypeptide chains, and a troponin unit with three globular units per 40 nm [42](#page=42). * **Myosin filaments:** These are the main component of the A-band and are arranged parallel to each other. Myosin consists of a long, elongated portion (tail) and a globular portion at one end (head). Myosin can be dissociated into light meromyosin (the largest part of the tail) and heavy meromyosin (the entire head and a small part of the tail) [42](#page=42). During contraction, actin filaments slide between myosin filaments. During relaxation, actin filaments cover only a small portion of the myosin, with an H-zone present [42](#page=42). > **Tip:** The distance between two Z-discs is the sarcomere, which is the smallest contractile unit. The Z-disc is formed in the middle of the I-band where adjacent actin filaments overlap. The Mittelscheibe is a zone in the middle of the H-zone where parts of myosin and actin overlap [43](#page=43). #### 6.2.3 Triad structure The triad structure is a well-developed sarcoplasmic reticulum that surrounds myofibrils as a branched membranous network, concentrating calcium ions. T-tubules are tubular invaginations of the sarcolemma that transmit action potentials to the sarcoplasmic reticulum. A triad consists of a central T-tubule with two terminal cisternae of the sarcoplasmic reticulum [43](#page=43). #### 6.2.4 Muscle contraction: sliding filament principle Muscle contraction follows the sliding filament principle, where actin and myosin filaments slide past each other [43](#page=43). The process involves the following steps: 1. An action potential from a motor neuron reaches the muscle at the motor end plate, releasing acetylcholine onto nicotinic receptors [43](#page=43). 2. Acetylcholine increases permeability to sodium, causing depolarization [43](#page=43). 3. Electrical changes (depolarization) are transmitted via T-tubules to the sarcoplasmic reticulum [43](#page=43). 4. Calcium ions are released from the sarcoplasmic reticulum, leading to calcium-dependent calcium release [43](#page=43). 5. Calcium ions bind to troponin C on the actin filament [43](#page=43). 6. Tropomyosin shifts deeper into the F-actin groove, causing a conformational change and freeing up binding sites for myosin on actin [43](#page=43). 7. A free myosin head binds to an actin monomer, with an ATP molecule attached to the myosin head [43](#page=43). 8. ATP hydrolysis ($ATP \rightarrow ADP + Pi + energy$) provides energy for the power stroke [43](#page=43). 9. The power stroke involves the bending of heavy meromyosin, pulling actin filaments over myosin filaments [44](#page=44). 10. Re-binding of ATP to the myosin head releases it from the previous actin monomer, allowing it to bind to another actin monomer [44](#page=44). Relaxation occurs when calcium is pumped back into the sarcoplasmic reticulum via a $Ca^{2+}/Mg^{2+}-ATP-ase$ pump. Without calcium, binding sites are not available for contraction due to the tropomyosin thread [44](#page=44). #### 6.2.5 Innervation of skeletal muscle Skeletal muscles are innervated by motor nerves of the voluntary nervous system [44](#page=44). * **Motor nerves:** These connect at the motor end plate, where neurotransmitters are exchanged for nicotinic receptors. A single nerve fiber branches to innervate multiple muscle fibers. Spatial summation, involving the recruitment of multiple muscle fibers based on intensity, increases force. Temporal summation involves a series of closely spaced stimuli from the same neuron, which reinforce each other [44](#page=44). * **Muscle spindle:** These are sensory receptors within muscles containing nuclear bag fibers (dynamic) and nuclear chain fibers (static), both with contractile proteins at their ends. Nerve fibers from muscle spindles lead to the central nervous system [44](#page=44). * **Golgi tendon organs:** These are located in the muscle tendons [44](#page=44). #### 6.2.6 Variants of skeletal muscle fibers Skeletal muscle fibers can be classified into several types based on their metabolic and contractile properties: * **Red muscle fibers:** These are highly vascularized and capillaries, ensuring abundant oxygen supply. They are thinner with fewer myofibrils and more mitochondria rich in cristae. They exhibit slow, intense contractions through oxidative phosphorylation and are suited for prolonged, low-intensity exercise [45](#page=45). * **White muscle fibers:** These include type 2 (a mix of sprint and aerobic capacity) and type 2b (pure sprint fibers). They are thicker with more myofibrils and fewer mitochondria. They produce fast, short-duration contractions via anaerobic glycolysis and are suited for short bursts of high-intensity exercise [45](#page=45). * **Intermediate forms:** These represent a mix of properties between red and white fibers [45](#page=45). > **Note:** In humans, all three types of fibers are combined within a single skeletal muscle. Aerobic training increases type I fibers, while strength training increases type II fibers. Transition between type I and type II is not possible, but changes between subtypes of type II (e.g., IIa to IIb) can occur [45](#page=45). #### 6.2.7 Regeneration of skeletal muscle tissue Skeletal muscle tissue possesses a reserve of myoblasts, called satellite cells, that did not fuse during embryonic development. These reserve cells lie adjacent to muscle bundles and are enveloped by the same basal membrane as the muscle fibers they are near. Following injury, macrophages clear debris. If the basal membrane remains intact, the muscle fiber regenerates itself. If the basal membrane is damaged, satellite cells divide and fuse with the muscle fiber [45](#page=45). #### 6.2.8 Modifications of skeletal muscle * **Intense exercise:** Leads to satellite cell division, with daughter cells fusing to existing muscle fibers, resulting in muscle hypertrophy (larger muscle mass). The amount of contractile proteins within existing fibers increases, and the amount of connective tissue in the perimysium also increases [45](#page=45). * **Immobilization:** Results in the breakdown of fiber proteins and a decrease in fiber diameter, leading to muscle atrophy (smaller muscle mass). Complete sarcomeres are broken down during prolonged periods in a shortened position. The amount of connective tissue decreases [45](#page=45). ### 6.3 Cardiac muscle tissue Cardiac muscle tissue forms the wall of the heart and is responsible for rhythmically and continuously pumping blood through the circulatory system [46](#page=46). #### 6.3.1 Cellular connections and microscopic structure Individual cardiac muscle cells are connected by gap junctions and nexuses, enabling specific communication and functional unity [46](#page=46). * **Transverse section:** Shows centrally located nuclei and radially arranged fields of Cohnheim. Loose connective tissue with numerous capillaries is found between cardiac muscle fibers [46](#page=46). * **Longitudinal section:** Reveals branched muscle fibers and intercalary discs, which have a staircase-like structure [46](#page=46). #### 6.3.2 Electron microscopy of cardiac muscle * **Contractile proteins:** Actin and myosin are specially ordered, identical to skeletal muscle cells, and tropomyosin and troponin are present [46](#page=46). * **Diad structure:** Terminal cisternae of the sarcoplasmic reticulum are less developed and smaller T-tubules are present, covered by a continuous basal lamina. This results in a diad structure, where a T-tubule makes contact with only one terminal cisterna [46](#page=46). * **Intercalary discs:** These are the cell boundaries of individual cardiac muscle cells. The transverse portion contains fasciae adherentes and desmosomes for firm attachment between cells, similar to zonulae adherentes where actin filaments attach. The longitudinally oriented portion consists of nexuses for information transfer [46](#page=46). * **Other elements:** Cardiac muscle contains numerous mitochondria, glycogen granules, and sometimes lipofuscin granules (age pigment) [47](#page=47). #### 6.3.3 Cardiac muscle contraction Cardiac muscle contraction is largely identical to skeletal muscle contraction, with a few key differences [47](#page=47). 1. Calcium for contraction in cardiac muscle comes from both the sarcoplasmic reticulum and extracellularly [47](#page=47). 2. The impulse is generated and transmitted by pacemaker cells and Purkinje cells [47](#page=47). #### 6.3.4 Innervation and Purkinje cells Cardiac muscle is autonomous, possessing cells that spontaneously depolarize, known as pacemaker cells or Purkinje cells. Parasympathetic and orthosympathetic innervation modifies heart rate and pumping force. Purkinje cells conduct impulses throughout the heart, are large and chain-like, contain few contractile elements, have abundant glycogen, and few, small mitochondria, making them dependent on oxygen. They have underdeveloped sarcoplasmic reticulum and no T-tubules. Intercalary discs, rich in desmosomes, connect these cells, and a connective tissue sheath protects them from other cardiac muscle cells, with the last Purkinje cell contacting a cardiac muscle cell [47](#page=47). #### 6.3.5 Regeneration of cardiac muscle tissue Cardiac muscle tissue regeneration is not possible. Ischemia leads to cell death, and the tissue is replaced by connective tissue, reducing elasticity [47](#page=47). ### 6.4 Smooth muscle tissue Smooth muscle tissue consists of cells that contract involuntarily [47](#page=47). #### 6.4.1 Structure and function Smooth muscle forms layers around hollow organs, controlling the size and movement of lumina in the cardiovascular, gastrointestinal, urogenital, and respiratory systems. There are two types [48](#page=48): * **Multi-unit:** Cells act individually, as seen in blood vessels for blood pressure control [48](#page=48). * **Single-unit:** Cells act in a pseudo-syncytial organization, as in the intestines for bowel movements [48](#page=48). Light microscopy shows individual spindle-shaped cells with centrally located nuclei. Myofilaments are present but lack striations. Single-unit smooth muscle contains nexuses [48](#page=48). #### 6.4.2 Electron microscopy of smooth muscle * **Contractile proteins:** Actin and myosin filaments are present but not regularly arranged. Tropomyosin is present, and attachment sites in the cytoplasm and on the cell membrane anchor actin, similar to Z-lines. Troponin is absent; calcium ions bind to calmoduline, a single polypeptide chain similar to troponin C [48](#page=48). * **Sarcoplasmic reticulum:** The plasma membrane contains caveolae, small invaginations that connect to contractile proteins. The sarcoplasmic reticulum is weakly developed, with the largest portion of calcium being extracellular [48](#page=48). * **Other elements:** There is a filament-free zone around the nucleus containing glycogen, mitochondria, ribosomes, and glycogen. Older cells may contain lipofuscin granules. Contact via gap junctions coordinates synchronous contraction. Collagenous and reticular fibrils surround each smooth muscle cell [48](#page=48). #### 6.4.3 Smooth muscle contraction During smooth muscle contraction, the plasma membrane and nucleus change shape, causing the muscle cell to shorten and thicken [48](#page=48). The process involves: 1. An action potential is transmitted to the smooth muscle cell via the autonomic nervous system [48](#page=48). 2. Intracellular calcium concentration increases, primarily from extracellular sources [49](#page=49). 3. Calcium binds to calmoduline, activating light chain myosin kinase (an enzyme) [49](#page=49). 4. Phosphorylation of the light chain of myosin allows it to interact with actin [49](#page=49). 5. A sliding filament principle is engaged [49](#page=49). 6. Contraction is transmitted to attachment points, allowing for synchronous contraction [49](#page=49). Relaxation occurs when the kinase is dephosphorylated and deactivated [49](#page=49). #### 6.4.4 Innervation of smooth muscle tissue Smooth muscle is influenced by parasympathetic and orthosympathetic neurons. Nerve fibers terminate in bulges (synapses) from which neurotransmitters can be released, such as muscarine. The entire surface of the plasma membrane is excitable [49](#page=49). #### 6.4.5 Regeneration of smooth muscle Smooth muscle regeneration is not possible [49](#page=49). --- # Ground substance and tissue fluid in connective tissue This section details the components and functions of the ground substance and tissue fluid within connective tissues, which are crucial for supporting and nourishing cells and fibers. ### 8.1 Ground substance The ground substance is a gel-like material within the extracellular matrix where connective tissue fibers are embedded. It is colorless, transparent, and homogeneous, with a viscous consistency that helps prevent the entry of foreign particles [12](#page=12). #### 8.1.1 Components of ground substance The ground substance is primarily composed of glycosaminoglycans (GAGs) and structural glycoproteins [12](#page=12). ##### 8.1.1.1 Glycosaminoglycans (GAGs) GAGs are linear polysaccharides formed from long chains of disaccharides [12](#page=12). * **Disaccharides:** These consist of uronic acid and hexosamine [12](#page=12). * **Covalent Bonding:** They are covalently linked to a protein core, except for hyaluronic acid [12](#page=12). * **Hydrophilic and Polyanionic Nature:** GAGs contain hydroxyl, carboxyl, and sulfate groups, making them strongly hydrophilic and behave as polyanions. They exhibit significant binding with sodium ions (Na+) [12](#page=12). * **Major Proteoglycans:** The most important proteoglycans are bound to dermatan sulfate, chondroitin sulfate, or heparan sulfate [12](#page=12). * **Synthesis:** The protein component of proteoglycans is synthesized in the rough endoplasmic reticulum (RER), glycosylation begins in the RER and is completed in the Golgi apparatus, and sulfation occurs in the Golgi apparatus [12](#page=12). * **Degradation:** Proteoglycans are degraded by lysosomal enzymes in various cell types and have a high turnover rate [12](#page=12). * **Principal Glycosaminoglycans:** * Hyaluronic acid (found in cartilage, umbilical cord, etc.) [12](#page=12). * Dermatan sulfate (found in organ capsules, structures with collagen fibers, etc.) [12](#page=12). * Chondroitin 4- or 6-sulfate (found in hyaline and elastic cartilage, etc.) [12](#page=12). * Heparan sulfate (found in structures with abundant reticular fibers) [12](#page=12). ##### 8.1.1.2 Structural glycoproteins These proteins contain carbohydrates and are characterized by a dominant protein component. They also contain non-linear polysaccharide chains of disaccharides, always including glycosamine, with a branched carbohydrate structure [12](#page=12). * **Key glycoproteins:** * Fibronectin: Plays a role in the adhesion of connective tissue cells and extracellular material [12](#page=12). * Laminin: Involved in the adhesion of epithelium to the basal lamina [12](#page=12). ### 8.2 Tissue fluid Tissue fluid is the fluid found in the interstitial spaces of tissues. It is present in small quantities [13](#page=13). #### 8.2.1 Function of tissue fluid The primary function of tissue fluid is transport [13](#page=13). * **Waste Removal:** It carries waste products from cells to the bloodstream for excretion or detoxification [13](#page=13). * **Nutrient and Oxygen Supply:** It transports oxygen from the bloodstream to the cells [13](#page=13). #### 8.2.2 Composition of tissue fluid Tissue fluid contains ions and soluble substances, similar in composition to blood plasma, along with low-molecular-weight proteins [13](#page=13). #### 8.2.3 Formation of tissue fluid The formation of tissue fluid is driven by two opposing pressures within blood vessels [13](#page=13): * **Hydrostatic Pressure:** This is the pressure exerted by blood flow on the blood vessel walls, forcing water and ions out of the capillaries [13](#page=13). * **Colloid-Osmotic Pressure:** This pressure arises from the proteins in blood plasma that cannot pass through the blood vessel walls. These proteins create an osmotic gradient that draws water and ions back into the blood vessels [13](#page=13). **Conclusion:** These two pressures generally balance each other, with a net pressure directed into the tissue [13](#page=13). > **Tip:** The pressure dynamics within blood vessels are crucial for understanding how tissue fluid is formed and how it interacts with the blood. A balance is maintained to prevent excessive fluid accumulation in the interstitial space. --- The ground substance and tissue fluid are crucial extracellular components of connective tissue, providing structural support, facilitating transport, and influencing cellular activities. ### 8.1 Components of ground substance The ground substance is the amorphous, gel-like material filling the space between cells and fibers in connective tissue, and it is largely composed of water, proteoglycans, glycosaminoglycans (GAGs), and non-collagenous proteins [24](#page=24). #### 8.1.1 Water Water is the primary component of the ground substance, accounting for a significant portion of its volume and playing a vital role in its hydration and functional properties, particularly in cartilage. The regulation of water content is essential for tissue function and is influenced by synthesis activity, nutrient supply, the piezoelectric effect, and mechanical loading/unloading cycles [24](#page=24) [25](#page=25). #### 8.1.2 Glycosaminoglycans (GAGs) GAGs are long, unbranched polysaccharide chains that are negatively charged due to their sulfate and carboxyl groups. This high negative charge allows GAGs to bind large amounts of water and cations like sodium and calcium, contributing to the tissue's ability to resist compression and maintain hydration [24](#page=24). * **Hyaluronic acid:** A particularly long and non-sulfated GAG that serves as a central backbone for proteoglycans, forming large proteoglycan aggregates [24](#page=24). * **Sulfated GAGs:** Include chondroitin sulfate and keratan sulfate, which are covalently attached to core proteins to form proteoglycans [24](#page=24). #### 8.1.3 Proteoglycans Proteoglycans are large molecules composed of a core protein to which multiple GAG chains are attached. They are essential for the structural integrity and functional properties of the ground substance [24](#page=24). * **Proteoglycan aggregates:** Multiple proteoglycans can bind to a single hyaluronic acid molecule, creating massive structures that occupy significant space and bind substantial amounts of water and ions [24](#page=24). * **Net-forming proteins:** These proteins, also known as link proteins, help to anchor proteoglycans to the hyaluronic acid backbone [24](#page=24). #### 8.1.4 Non-collagenous fibers These fibers contribute to the stability of the ground substance and are often incorporated into proteoglycan aggregates. They play a role in linking cells to the matrix and to collagenous fibrils [24](#page=24). ### 8.2 Tissue fluid and its role Tissue fluid, also known as interstitial fluid, is the fluid component of the extracellular matrix that bathes the cells of connective tissue. It is derived from blood plasma and plays a critical role in transporting nutrients, gases, and waste products to and from the cells [23](#page=23) [25](#page=25). #### 8.2.1 Transport mechanisms The movement of tissue fluid and its constituents is influenced by several factors: * **Diffusion:** Essential for the transport of small molecules like oxygen, nutrients, and waste products to and from cells [25](#page=25). * **Piezo-electric effect:** Mechanical loading can induce electrical potential changes that stimulate nutrient and oxygen transport to chondrocytes in cartilage [25](#page=25). * **Pressure gradients:** During loading and unloading of connective tissues, particularly cartilage, pressure differences drive the movement of water and ions. This phenomenon, known as visco-elasticity, allows for fluid exchange between the tissue and surrounding compartments [25](#page=25). #### 8.2.2 Water balance in connective tissue (e.g., cartilage) The water content of connective tissues, especially articular cartilage, is tightly regulated. * **Synthesis activity:** The synthesis of matrix components by cells directly influences water binding and retention [25](#page=25). * **Nutrient supply:** Adequate supply of oxygen, amino acids, and glucose is necessary for matrix synthesis and is dependent on diffusion from sources like synovial fluid [25](#page=25). * **Mechanical forces:** * **Creep:** Refers to the time-dependent deformation of the collagen network under sustained load, influenced by the rate of water extrusion [26](#page=26). * **Stress-relaxation:** Describes the decrease in stress over time when a tissue is held at a constant strain, due to the fluid redistribution within the tissue [26](#page=26). * **Regeneration and repair:** The fluid dynamics and composition of the extracellular matrix are critical for tissue repair processes [28](#page=28). > **Tip:** In articular cartilage, the interplay between mechanical loading and the composition of the ground substance is vital for maintaining tissue health. Disruptions to this balance can lead to degeneration and conditions like osteoarthritis [26](#page=26). ### 8.3 Ground substance and tissue fluid in specific connective tissues The composition and function of ground substance and tissue fluid vary depending on the specific type of connective tissue. #### 8.3.1 Articular cartilage In articular cartilage, the ground substance is rich in proteoglycans and GAGs, which are crucial for its ability to withstand compressive forces and reduce friction. The water content is high, contributing to its shock-absorbing properties. Synovial fluid also plays a vital role in lubricating the cartilage surface and providing nutrients [23](#page=23) [25](#page=25) [28](#page=28). #### 8.3.2 Bone tissue While bone has a mineralized extracellular matrix, it also contains a small amount of ground substance composed of proteoglycans. This ground substance plays a role in the mineralization process and the regulation of calcium and phosphate levels. Tissue fluid within the lacunae and canaliculi of bone facilitates the exchange of nutrients and waste products between osteocytes and blood vessels [32](#page=32) [33](#page=33). #### 8.3.3 Loose connective tissue In loose connective tissue, the ground substance is more hydrated and less dense than in cartilage or bone. It is composed of hyaluronic acid, proteoglycans, and glycoproteins. This fluid matrix supports cells, facilitates diffusion, and allows for immune cell migration [23](#page=23). #### 8.3.4 Synovial fluid Synovial fluid is a specialized fluid found within synovial joints. It is a dialysate of blood plasma, enriched with hyaluronic acid and glycoproteins secreted by synovial membrane cells. Its primary functions are lubrication, shock absorption, and nutrient supply to the avascular articular cartilage [28](#page=28) [37](#page=37). --- The ground substance and tissue fluid of connective tissue are the non-cellular components that fill the space between cells and fibers, playing crucial roles in structural support, diffusion, and cell communication. ### 8.1 Composition and structure of ground substance The ground substance is an amorphous, gel-like material that occupies the interstitial space within connective tissue. It is primarily composed of glycosaminoglycans (GAGs), proteoglycans, and glycoproteins [44](#page=44). #### 8.1.1 Glycosaminoglycans (GAGs) GAGs are long, unbranched polysaccharide chains made up of repeating disaccharide units. They are highly negatively charged due to the presence of sulfate and carboxyl groups, which attract cations (like sodium) and subsequently water. This property is critical for the hydration and turgor of the connective tissue [44](#page=44). * **Hyaluronic acid:** The largest and most abundant GAG, it is not sulfated and is not covalently bound to proteins. It contributes significantly to the viscosity of the ground substance [44](#page=44). * **Chondroitin sulfate:** A sulfated GAG, typically found in cartilage, bone, and skin [44](#page=44). * **Dermatan sulfate:** Found in skin, tendons, and heart valves [44](#page=44). * **Heparan sulfate:** Present in basement membranes and on cell surfaces [44](#page=44). * **Keratan sulfate:** Primarily found in cartilage and the cornea [44](#page=44). #### 8.1.2 Proteoglycans Proteoglycans are complex macromolecules consisting of a core protein covalently linked to one or more GAG chains. They are responsible for organizing the GAGs and can influence cell behavior. Examples include aggrecan (found in cartilage) and decorin (found in connective tissues, interacting with collagen) [44](#page=44). #### 8.1.3 Glycoproteins Glycoproteins are proteins with short, branched carbohydrate chains attached. They are involved in cell adhesion, migration, and differentiation [44](#page=44). * **Fibronectin:** A major adhesive glycoprotein that links cells to the extracellular matrix, particularly collagen and GAGs. It plays a role in cell shape, migration, and wound healing [44](#page=44). * **Laminin:** Primarily found in basement membranes, it mediates cell adhesion and influences cell differentiation and survival [44](#page=44). The tissue fluid, also known as interstitial fluid, is derived from blood plasma and bathes the connective tissue cells and fibers. It is essentially a filtrate of blood that has leaked out of capillaries [44](#page=44). #### 8.2.1 Formation and composition Tissue fluid is formed as plasma ultrafiltrates through the capillary walls, driven by hydrostatic and osmotic pressure gradients. It contains water, small solutes (ions, glucose, amino acids, fatty acids), oxygen, nutrients, and waste products. Large molecules like plasma proteins are generally retained within the blood vessels due to their size and the properties of the capillary endothelium [44](#page=44). #### 8.2.2 Role in transport and exchange The tissue fluid acts as a medium for the exchange of substances between the blood and the cells [44](#page=44). * **Nutrient and oxygen delivery:** It transports oxygen and nutrients from the capillaries to the connective tissue cells. * **Waste removal:** It carries metabolic waste products and carbon dioxide from the cells to the capillaries and lymphatic vessels. * **Immune surveillance:** It transports immune cells and antibodies throughout the tissue. #### 8.2.3 Lymphatic drainage Excess tissue fluid, along with some larger molecules and cellular debris, is collected by the lymphatic system, forming lymph. This prevents tissue edema and returns fluid to the circulatory system [44](#page=44). ### 8.3 Functional significance The ground substance and tissue fluid are critical for maintaining tissue integrity and function: * **Structural support:** The hydration of GAGs provides turgor and resistance to compression [44](#page=44). * **Diffusion barrier:** While acting as a medium for diffusion, the viscosity of the ground substance can also regulate the rate of movement of molecules [44](#page=44). * **Cell signaling and communication:** Glycoproteins and proteoglycans embedded within the ground substance can bind to growth factors and receptors, influencing cell behavior [44](#page=44). * **Lubrication:** In joints, synovial fluid, a specialized form of tissue fluid, lubricates the articulating surfaces [44](#page=44). --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |------|------------| | Autonomic Nervous System | A division of the nervous system that regulates involuntary bodily processes such as smooth muscle contraction, glandular secretion, and heart rate, operating unconsciously. | | Axon | A long, cylindrical projection of a neuron responsible for conducting nerve impulses away from the cell body to other cells, often covered by a myelin sheath. | | Axon Hillock | A short, pyramid-shaped protrusion where the axon originates from the perikaryon (cell body) of a neuron. | | Axoplasm | The cytoplasm within an axon, which is relatively poor in cellular organelles compared to the perikaryon. | | Bipolar Neuron | A type of neuron characterized by having one axon and one dendrite extending from the cell body. | | Cell Body (Perikaryon) | The metabolic center of a neuron, containing the nucleus and surrounding cytoplasm, which is sensitive to stimuli and responsible for maintaining the cell. | | Central Nervous System (CNS) | The part of the nervous system comprising the brain and spinal cord, responsible for processing and integrating information. | | Chemical Synapse | A junction between two nerve cells where signal transmission occurs via the release of neurotransmitters from the presynaptic neuron into the synaptic cleft, which then bind to receptors on the postsynaptic neuron. | | Dendrite | Branched extensions of a neuron that receive stimuli from the environment or other neurons and transmit impulses toward the cell body. | | Electrical Synapse | A direct connection between two cells, typically through gap junctions (nexuses), allowing for the bidirectional exchange of ions and low-molecular-weight substances. | | Endoneurium | A thin layer of loose connective tissue found between nerve fibers within a nerve. | | Epineurium | The outermost, fibrous layer of dense connective tissue that surrounds a nerve. | | Mucoid Connective Tissue | A gelatinous tissue characterized by an excess of amorphous ground substance, predominantly branched and cohesive fibroblasts, a resilient-elastic nature, and abundant collagen fibers. It is primarily found in the embryonic period, such as in the umbilical cord, where it contains lymphatic vessels, arteries, and veins, preventing kinking due to its jelly-like structure. | | Hematopoietic Tissue | Tissue containing hematopoietic stem cells (HSCs) that give rise to other blood cells. Hematopoiesis, or blood formation, occurs in red bone marrow, originating from the mesoderm. It involves the production of mature blood cells from a limited number of multipotent HSCs to meet enormous production demands, with two main lines: myeloid (macrophages, neutrophils, basophils, erythrocytes) and lymphoid (T-cells, B-cells, natural killer cells). | | Loose Connective Tissue | A tissue with an ethereal structure that fills spaces between muscle fibers and fascia, supports epithelium in glands and mucous membranes, and surrounds blood and lymphatic vessels. Its cellular component predominates, typically with macrophages and fibroblasts, and it contains collagenous, elastic, and reticular fibers with a less prominent ground substance. It is highly reactive and well-vascularized. | | Dense Connective Tissue | A tissue where collagen strongly dominates, with fewer cells and less deformability but significantly higher tensile strength. It is subdivided into unordered, where collagen fiber bundles run in all directions providing resistance to tension from all angles (e.g., dermis of the skin, submucosa of the intestine), and ordered, where collagen fibers are oriented along one or more main directions, providing resistance to tension in specific directions (e.g., Achilles tendon). | | Elastic Tissue | Connective tissue composed primarily of elastic fibers, though entirely elastic tissue does not occur. It features bundles of thick, fused thin elastic fibers with fibroblasts interspersed, offering great elasticity. It is found in structures like the yellow ligaments of the vertebral column and the suspensory ligament of the penis. | | Reticular Connective Tissue | Tissue constructed from reticular fibers and reticulum cells, forming the ground structure of blood-forming bone marrow and lymphoid tissue. It creates a network that supports and carries blood-forming cells. Reticulum cells have large nuclei with finely dispersed chromatin and are connected via cytoplasmic extensions, with minimal phagocytic activity. | | Hyaline Cartilage | A type of cartilage found in articular surfaces, rib cartilage, the nose, larynx, trachea, bronchi, and the embryonic skeleton. It consists of cells called chondrocytes, located in lacunae (small cavities), which are round with a large central nucleolus and many nucleoli. The extracellular material includes collagen type II fibers and ground substance composed of proteoglycans and glycosaminoglycans. It is surrounded by a perichondrium, a layer of dense connective tissue containing stem cells. | | Chondrocyte | Mature cartilage cells that reside in lacunae within the extracellular matrix of cartilage. They are typically round with a large central nucleolus and numerous nucleoli, possessing many cytoplasmic projections that increase their surface area. Their cytoplasm is rich in ribosomes, has an extensive rough endoplasmic reticulum (RER), a large Golgi apparatus, and abundant mitochondria. | | Perichondrium | The outer layer surrounding hyaline and elastic cartilage, containing stem cells responsible for cartilage growth. It is a layer of dense connective tissue, often containing type I collagen and/or elastin, with fibroblasts that can differentiate into chondrocytes. It also contains blood vessels, lymphatic vessels, and nerve elements, facilitating nutrient supply through diffusion. | | Articular Cartilage | A specialized connective tissue found in all synovial joints of the body, covering the bone structures to enable friction-free movement. Its functions include absorbing shock and compression forces as a buffer and reducing friction between joint partners, supported by synovial fluid. It is organized into deep, middle, and superficial tangential zones based on fiber orientation. | | Matrix | The structural material that forms part of tissues and is located outside the cells. In articular cartilage, it comprises water, collagen type II fibers forming a meshwork, non-collagenous fibers for stability, and proteoglycans and glycosaminoglycans. These components contribute to the cartilage's resilience and ability to withstand mechanical forces. | | Proteoglycans | Large molecules in the extracellular matrix composed of a central protein chain to which glycosaminoglycans (GAGs) are attached. GAGs can bind water, sodium, and calcium ions, making them strongly negatively charged. Multiple proteoglycans can bind to a hyaluronic acid chain, forming proteoglycan aggregates. | | Water Regulation | The process by which the amount of water within articular cartilage is controlled, influencing its hydration and mechanical properties. This is influenced by factors like synthesis activity and nutrient supply. | | Synthesis Activity | The metabolic process by which chondrocytes (cartilage cells) produce and secrete extracellular matrix components, such as proteoglycans and glycosaminoglycans (GAGs), which is crucial for maintaining cartilage health and regulating water content. | | Nutrient Supply | The provision of essential substances like oxygen, amino acids, and glucose to chondrocytes, primarily through diffusion from the synovial fluid, which is vital for macromolecule synthesis and cartilage maintenance. | | Piezo-electric Effect | The generation of an electric charge in response to applied mechanical stress. In articular cartilage, alternating loading can create electrical potential fluctuations that stimulate chondrocytes to synthesize matrix, aiding tissue organization. | | Loading and Unloading | The cyclical application and removal of mechanical forces on articular cartilage. Loading causes the cartilage to deform and expel water, while unloading allows it to rehydrate, a process contributing to its visco-elastic behavior. | | Visco-elasticity | The property of a material that exhibits both viscous (fluid-like) and elastic (solid-like) characteristics when undergoing deformation. In cartilage, this is due to the movement of water and ions within the matrix under load. | | Creep | A time-dependent deformation of a material under a constant applied stress. In articular cartilage, creep occurs due to the deformation of the collagen network and the movement of water and ions within the matrix. | | Stress-relaxation | A phenomenon where the stress in a viscoelastic material decreases over time while the strain remains constant. In cartilage, this is caused by the movement of water through the tissue until an equilibrium pressure is reached. | | Degeneration | The deterioration of articular cartilage, often associated with aging, overuse, or injury. This can lead to reduced synthesis activity, changes in matrix composition, and impaired water binding. | | Osteoarthritis | A degenerative joint disease characterized by the breakdown of articular cartilage, leading to pain, stiffness, and reduced mobility. It can be caused by factors such as aging, injury, and mechanical overload. | | Tidemark | A distinct boundary within articular cartilage that separates the superficial, softer zone from the deeper, mineralized zone. A shift in the tidemark towards the surface can indicate a progression of ossification. | | Bone tissue | A type of connective tissue that forms the bones of the body, characterized by being rich in inorganic crystals within the bone matrix, containing blood vessels and nerves, and being a living tissue that undergoes permanent remodeling and is metabolically active. | | Compact bone | A region of bone tissue that is dense and lacks visible cavities, forming the outer layer of bones. | | Spongy bone | A region of bone tissue characterized by a network of bone struts (trabeculae) and cavities, which often contains blood-forming cells (bone marrow). | | Lamellar bone | The mature form of bone tissue that develops from woven bone, organized into layers called lamellae. | | Osteon (Haversian system) | A structural unit of compact bone consisting of concentric lamellae arranged around a central Haversian canal. | | Haversian canal | A central canal within an osteon that contains blood vessels and nerves, facilitating the nourishment and innervation of the bone tissue. | | Volkmann's canals | Perforating canals that connect Haversian canals to each other and to the periosteum or endosteum, allowing for the passage of blood vessels and nerves. | | Interstitial lamellae | Bone lamellae that fill the spaces between osteons, representing remnants of older osteons that have been partially resorbed. | | Periosteum | A dense layer of vascular connective tissue enveloping the bones, except at the surfaces of the joints. | | Endosteum | A thin layer of connective tissue lining the inner surface of the bony tissue that forms the medullary cavity of long bones. | | Woven bone (Pexiform bone) | An immature form of bone tissue with a less organized structure, where collagen fibers are arranged in various directions and osteocytes are uniformly distributed. | | Osteoblast | A bone-forming cell responsible for synthesizing new bone matrix (osteoid) and initiating ossification. | | Osteoid | The unmineralized extracellular matrix of bone, composed of collagen fibers and ground substance, which is subsequently mineralized to form bone tissue. | | Osteoblasts | Bone-forming cells derived from mesenchymal cells that synthesize and secrete osteoid, the organic components of bone matrix. | | Osteocytes | Mature bone cells that are derived from osteoblasts and are embedded within the calcified bone matrix, playing a role in bone maintenance and remodeling. | | Desmal Ossification | Direct bone formation where mesenchymal tissue is directly converted into bone without the intermediate formation of cartilage. | | Chondral Ossification | Indirect bone formation that involves cartilage as an intermediate stage, typically seen in the development of long bones. | | Perichondral Ossification | A process of bone formation occurring on the outer surface of cartilage, similar to desmal ossification, where a bone collar is formed around the cartilage model. | | Endochondral Ossification | The process by which cartilage is gradually replaced by bone, a primary mechanism for the formation of long bones and other skeletal elements. | | Diaphysis | The shaft or central part of a long bone, which is the primary site of ossification during endochondral bone formation. | | Epiphysis | The expanded end of a long bone, which articulates with another bone at a joint and is a secondary site of ossification. | | Growth Plate Zone | A layer of hyaline cartilage within the epiphysis of a long bone that is responsible for longitudinal bone growth; it is characterized by parallel columns of chondrocytes. | | Osteogenic Bud | A vascularized connective tissue bud that invades the calcified cartilage matrix during endochondral ossification, carrying osteoblasts and blood vessels to the developing bone. | | Primary Medullary Cavity | The initial hollow space formed within the diaphysis of a long bone during endochondral ossification, which will eventually become the site of bone marrow. | | Collagen fibers | These are the most abundant protein fibers in mammals, characterized by their high tensile strength and non-elastic nature. They are composed of tropocollagen units linked head-to-tail and laterally, often appearing wavy, which contributes to the extensibility of tissues like skin. | | Tropocollagen | The fundamental building block of collagen fibers, consisting of a triple helix structure. These units link together in a staggered, head-to-tail arrangement, and also associate laterally, to form the larger collagen fibrils. | | Reticular fibers | A specialized, thinner type of collagen fiber, primarily composed of collagen type III, glycoproteins, and proteoglycans. They provide structural support to cells in various tissues, such as the bone marrow during hematopoiesis. | | Elastin | A globular protein that polymerizes to form elastic fibers. It provides tissues with the ability to stretch and recoil, contributing to their tensile strength and deformability. | | Elastic fibers | These fibers are thinner and straighter than collagen fibers, forming a network that can fuse at junctions. They consist of an amorphous central mass of elastin surrounded by a sheath of tubular microfibrils, allowing for tissue elasticity. | | Ground substance | A gel-like material within the extracellular matrix where fibers are embedded. It is colorless, transparent, homogeneous, and viscous, playing a role in preventing the entry of foreign particles and providing hydration. | | Glycosaminoglycans (GAGs) | Linear polysaccharides composed of repeating disaccharide units, forming long chains. They are strongly hydrophilic due to hydroxyl, carboxyl, and sulfate groups, and bind to Na+ ions, contributing to the osmotic properties of the ground substance. | | Hyaluronic acid | A prominent glycosaminoglycan found in cartilage and the umbilical cord, characterized by its long, unbranched chain structure and significant role in tissue hydration and lubrication. | | Dermatan sulfate | A glycosaminoglycan found in organ capsules and structures rich in collagen fibers, such as the dermis. It plays a role in tissue organization and mechanical resistance. | | Chondroitin 4- or 6-sulfate | A glycosaminoglycan predominantly found in hyaline and elastic cartilage, contributing to the tissue's ability to withstand intermittent pressure. | | Heparan sulfate | A glycosaminoglycan present in tissues with a high concentration of reticular fibers, such as the liver and lungs. It is involved in cell adhesion and signaling processes. | | Structural glycoproteins | Proteins that contain carbohydrate moieties, with the protein component being dominant. They have non-linear polysaccharide chains and play roles in cell adhesion and tissue organization. | | Adipokines | Cytokines secreted by adipose tissue, such as adiponectin and interleukins, which play roles in various physiological processes including metabolism and immunity. | | Calmoduline | A single polypeptide chain protein that binds calcium ions and activates enzymes, similar in function to troponin C in muscle contraction. | | Contractie | The process by which a muscle cell shortens or tightens, generating force. | | Glycogeenpartikels | Granules of stored glucose found within muscle cells, serving as an energy reserve for muscle activity. | | Hartspierweefsel | Muscle tissue found in the heart, characterized by branched fibers, intercalated discs, and involuntary rhythmic contractions to pump blood. | | Histogenese | The process of the development and formation of tissues, specifically referring to how different cell types, like adipocytes or muscle cells, originate and differentiate. | | Innervatie | The supply of nerves to a part of the body, crucial for transmitting signals that control muscle function, including contraction and relaxation. | | Intercalaire schijven | Specialized junctions between cardiac muscle cells that facilitate electrical coupling and mechanical adhesion, appearing as stepped structures. | | Lipofuscinekorrels | Age pigments or residual bodies found in older cells, representing accumulated waste products from cellular metabolism. | | Motorische eindplaat | The specialized synapse between a motor neuron and a muscle fiber, where neurotransmitters are released to initiate muscle contraction. | | Myofibrillen | The contractile elements within a muscle fiber, composed of repeating units of actin and myosin filaments that slide past each other during contraction. | | Myosinefilamenten | Thick filaments in muscle fibers composed primarily of the protein myosin, which interact with actin filaments to generate force during contraction. | | Tissue Fluid | The fluid found in the interstitial spaces of tissues, originating from blood plasma, which transports waste products from cells to the bloodstream and oxygen from the bloodstream to cells. | | Chondroitin Sulfate | A glycosaminoglycan primarily found in hyaline and elastic cartilage, important for the structural integrity and pressure resistance of these tissues. | | Fibronectin | A key structural glycoprotein involved in the adhesion of connective tissue cells to the extracellular material and plays a role in cell migration and differentiation. | | Laminin | A structural glycoprotein essential for the adhesion of epithelial cells to the basal lamina, providing a critical link between epithelial and connective tissues. | | Extracellular Matrix | The non-cellular component of connective tissue, consisting of fibers, ground substance, and tissue fluid, which provides structural support, mechanical strength, and regulates cellular activities. | | Hydrostatic Pressure | The pressure exerted by a fluid due to the force of gravity or flow, which in blood vessels, drives water and ions out of the capillaries into the surrounding tissue. |