STRUCTURE AND FUNCTION OF THE MUSCULOSKELETAL SYSTEM

Osteoblasts: Osteoblasts are cells derived from mesenchymal stem cells. Osteoblasts produce several substances, including osteocalcin, TGF-β (a growth inhibitor for many cells), macrophage colony-stimulating factor, receptor activator of nuclear factor κB-ligand, osteoprotegerin (OPG), and bone matrix⁷ and osteocalcin when stimulated by 1,25-dihydroxyvitamin D. Osteoblasts are active on the outer surface of bones, where they form a single layer of cells. They bring about the formation of new bone by their synthesis of osteoid (nonmineralized bone matrix). The mechanism of osteoblast stimulation is reported to be the production of so-called coupling factors generated during the resorption process. Osteoblasts bring about the formation of new bone and the orderly mineralization of bone matrix by concentrating some of the plasma proteins (growth factors) found in the bone matrix and by facilitating the deposit and exchange of calcium and other ions at the site. Osteoblasts alter levels of receptor activator of nuclear factor κB-ligand (RANKL) and OPG. The balance of these two cytokines determines overall osteoclast formation⁸ (see Figure 42-11). RANKL is part of a ligand-receptor system that assists in regulating osteoclastic bone remodeling. As new bone is formed it is shaped and remodeled through TGF-β, as well as other plasma proteins (growth factors) found in the bone marrow (Table 41-3).

Osteocytes communicate with other cells and appear to instruct both osteoclasts and osteoblasts about when and where to resorb and form bone.⁶ In contact with bone mineral, osteoclasts use adhesive structures, called podosomes, to attach themselves to the bone surface. They then seal their cytoplasm with the underlying bone and dissolve the bone and matrix while protecting the surrounding tissue.⁹ Thus the cells of the osteoblastic lineage (osteoblasts and osteocytes) form a network of cells in bone that sense the shape and structure of bone and determine where it is appropriate that bone be formed or resorbed, according to Wolfe’s law (bone is shaped according to its function).

Osteoblasts have an active state and a resting state. When active, osteoblasts synthesize and secrete osteoid. When in the resting state, they appear dormant. If appropriately stimulated, however, the resting osteoblasts are capable of resuming activity.

Osteocytes: An osteocyte is a transformed osteoblast that is trapped or surrounded in osteoid as it hardens from minerals that enter during ossification (see Figure 41-2, B). It is the final differentiation stage for an osteoblast. The osteocyte is within a space in the hardened bone matrix called a lacuna. Each osteocyte has a high nucleus/cytoplasm ratio with a thin layer of nonmineralized osteoid around it, similar to the egg white surrounding an egg yolk. Osteocytes secrete proteins, such as sclerostin (a Wnt antagonist that binds BMPs), that result in reduced bone formation.^4,7

The function of osteocytes is not fully known, but they communicate with each other and help concentrate nutrients in the matrix. Osteocytes obtain nutrients from capillaries in the canaliculi, which contain nutrient-rich fluids. Osteocytes also help synthesize and replace needed elements of the matrix by signaling both osteoclasts and osteoblasts to resorb and form new bone. Through exchanges between these cells, hormone catalysts, and minerals, optimal levels of calcium, phosphorus, and other minerals are maintained in blood plasma. The osteocyte also aids in modifying bone matrix through release of enzymes to dissolve the mineralized walls of the lacunae to prepare the bone for remodeling. (Remodeling is described on p. 1547.)

Osteoclasts: Osteoclasts are the major resorptive cells of bone. They are large multinucleated cells with a short life span. Osteoclasts develop from the hematopoietic stem cell in the bone marrow stroma⁸ and adjacent vessels and from mononuclear phagocytic cells. Osteoclasts contain lysosomes (digestive vacuoles) filled with hydrolytic enzymes. Fine projections, or microvilli, fan out from the osteoclast cell’s surface and are known as ruffled borders; these projections result from extensive infoldings of the cell membrane adjacent to the resorptive surface.¹⁰ Osteoclasts in regions of bone resorption lie in pits called Howship lacunae, where the infolded, ruffled borders of the osteoclasts greatly increase the surface area of the plasma membrane. The infolds end in numerous channels and vesicles in the cell cytoplasm, permitting them to resorb the bone under their ruffled, infolded borders.

Osteoclasts bind to the bone surface of cell attachment proteins called integrins.¹⁰ They bring about resorption of bone by secretion of hydrochloric acid (HCl) and cathepsin K (a protease enzyme),⁹ which help dissolve bone minerals and collagenase, which aids in digesting collagen, along with the action of cytokines (see Table 41-3). Matrix metalloproteinases (MMPs), a group of proteolytic enzymes, help control osteoclast-matrix interactions necessary for bone resorption.¹¹ Once resorption is completed, the osteoclast disappears by degeneration, either by reverting back to its parent cell or by leaving the site through the process of cell mobility, wherein the osteoclast then becomes an inactive, or “resting,” osteoclast.

Collagen Fibers: Collagen fibers are the major organic component of bone matrix. The fibers are approximately 90% type I collagen, which is synthesized and secreted by osteoblasts. Collagen-I is essential for bone strength. Once secreted, the collagen molecules assemble into thin chains called α-chains, which combine in threes to form fibrils. The fibrils form a staggered pattern, overlapping nearby fibrils by approximately one fourth their length. This staggered, overlapping pattern creates regular gaps, called hole zones, into which mineral crystals are deposited. After mineral deposition the fibrils link together and twist to form ropelike fibers. Collagen fibers then join to form a framework that gives bone its tensile strength and enables it to bear weight.

Collagen is the most abundant macromolecule in the body, accounting for approximately one third of all protein and providing the structural framework for nearly all tissues. Collagen is one of the extracellular components, along with proteoglycans and noncollagenous matrix proteins, of articular cartilage. To date, several types of collagen have been identified. Cartilage-specific collagens include types II (the principal component), VI, IX, X, and XI. Type IX collagen is thought to be the “glue” that holds together the type II collagen scaffold of articular cartilage, helps maintain the structural integrity of cartilage, and resists tensile forces on the joint cartilage. Type XI regulates the fibril diameter of type II cartilage. Degradation of type IX collagen by proteolytic enzymes has been seen in the early stages of osteoarthritis and rheumatoid arthritis. Researchers have proposed that this degradation, or “unplugging,” may be the mechanism for the degenerative changes seen in osteoarthritic and rheumatoid cartilage. Table 41-4 gives the musculoskeletal distribution of other types of collagen.

Proteoglycans: Proteoglycans are large complexes of numerous polysaccharides attached to a common protein core. Hyaline cartilage is primarily composed of the glycosaminoglycans chondroitin sulfate and keratin sulfate. They strengthen bone by forming compression-resistant networks between the collagen fibrils. Proteoglycans also control the transport and distribution of electrically charged particles (ions), particularly calcium, through the bone matrix, thereby playing a role in bone calcium deposition and calcification.

Glycoproteins: Glycoproteins are also carbohydrate-protein complexes of bone. Glycoproteins control the collagen interactions that lead to fibril formation. They also may play a role in calcification.

Some of the glycoproteins in bone matrix include bone sialoprotein, osteocalcin, osteonectin, laminin, albumin, and α-glycoprotein. Other proteins found in bone matrix are the compounds currently called bone morphogenic proteins (BMPs) (see Table 41-1). Sialoprotein (osteopontin) makes up about 8% of the noncollagenous matrix of bone and easily binds with calcium.

Osteocalcin is also a calcium-binding protein that binds preferentially to calcium that has already crystallized. The roles of osteocalcin may be to inhibit calcium phosphate precipitation and play a part in bone resorption by recruiting osteoclasts.

Osteonectin is also thought to bind calcium in bones, and laminin stabilizes basement membranes in bones. Laminin is an abundant bone matrix protein in humans that is most effective in neurite and axon growth.

Bone albumin is identical to serum albumin. In calcified matrix, bone albumin is permanently fixed to bone mineral crystals and remains so until the bone is resorbed. Researchers believe bone albumin transports essential elements such as hormones, ions, and other metabolites to and from the bone cells and maintains the osmotic pressure of bone fluid (fluid surrounding mineral crystals and osteoblasts).

α-Glycoprotein is thought to be synthesized in the liver, to be released into blood plasma, and to circulate to bone matrix, where it accumulates. α-Glycoprotein’s affinity for calcium is 40 times greater than that of albumin. Therefore, it probably plays an important role in the calcification of growing bone. α-Glycoprotein also may facilitate bone resorption by activating osteoclasts.

1. Hematoma formation: occurs if vessels have been damaged, causing hemorrhage. Fibrin and platelets within the hematoma form a meshwork that is the initial framework for healing with the help of hematopoietic growth factors such as platelet-derived growth factor and TGF-β (see Table 41-3).

2. Procallus formation: fibroblasts, capillary buds, and osteoblasts move into the wound to produce granulation tissue called procallus. Cartilage is formed as a precursor of bone, and types I, II, and III collagen are formed. Enzymes and growth factors, such as insulin and insulin-like growth factors, plus bone morphogenic protein and osteogenin, aid in this stage of healing.

3. Callus formation: osteoblasts in the procallus form membranous or woven bone (callus). Enzymes increase the phosphate content and permit the phosphate to join with calcium to be deposited as mineral to harden the callus.

4. Callus replacement: osteoblasts continue to replace the callus with lamellar bone or trabecular bone (Figure 41-6).

5. Remodeling: the periosteal and endosteal surfaces of the bone are remodeled to the size and shape of the bone before injury. Synthesis of other types of collagen recedes in favor of type I, which is the collagen found in bone. This final stage of healing, or remodeling, is vital because bone that has not been remodeled does not have good mechanical properties for weightbearing and mobility.

1. A fibrous joint capsule (articular capsule)

2. A synovial membrane that lines the inner surface of the joint capsule

3. A joint cavity (synovial cavity), a space formed by the capsule

4. Synovial fluid, which fills the joint cavity and lubricates the joint surface

5. Articular cartilage, which covers and pads the articulating bony surfaces

Joint Capsule: The fibrous joint capsule (articular capsule) is connective tissue that covers the ends of the bones where they meet in the joint. Sharpey fibers firmly attach the proximal and distal capsules to the periosteum and ligaments and tendons, which also reinforce the capsule. The joint capsule is made up of parallel, interlacing bundles of dense, white fibrous tissue. It is richly supplied with nerves, blood vessels, and lymphatic vessels. The nerves in and around the joint capsule are sensitive to the rate and direction of motion, compression, tension, vibration, and pain.

Synovial Membrane: The synovial membrane (synovium) is the smooth, delicate inner lining of the joint capsule (Figure 41-10). It lines the nonarticular portion of the synovial joint and any ligaments or tendons that traverse the joint cavity. It is made up of two layers—a vascular layer (subintima) and a thin cellular layer (intima). The vascular subintima merges with the fibrous joint capsule and is composed of loose fibrous connective tissue, elastin fibers, fat cells, fibroblasts, macrophages, and mast cells. The intima consists of rows of synovial cells embedded in a fiber-free intercellular matrix. The intima contains two types of synovial cells: type A and type B. Type A synovial cells ingest and remove bacteria and particles of debris by phagocytosis in the joint cavity. (Phagocytosis is described in Chapter 6.) Type B synovial cells secrete hyaluronate, a binding agent that gives synovial fluid its viscous quality. The synovial membrane is richly supplied with blood and lymphatic vessels; therefore, it is capable of rapid repair and regeneration.

Joint Cavity: The joint cavity (synovial cavity) is an enclosed fluid-filled space between the articulating surfaces of the two bones. This small cavity, often called the joint space, enables the two bones to move “against” one another. The synovial cavity is surrounded by the synovial membrane and filled with a clear, viscous, slick fluid called the synovial fluid.

Synovial Fluid: Synovial fluid is superfiltrated plasma from blood vessels in the synovial membrane. Synovial fluid lubricates the joint surfaces, nourishes the pad of the articular cartilage that covers the ends of the bones, and contains free-floating synovial cells and various leukocytes that phagocytose joint debris and microorganisms. Loss of synovial fluid leads to rapid deterioration of articular cartilage.

Articular Cartilage: Articular cartilage is a layer of hyaline cartilage that covers the end of each bone (Figure 41-11). It ranges from 2 to 5 mm thick, depending on the size of the joint, the fit of the two bone ends, and the amount of weight and shearing force the joint normally withstands. Cartilage strength and its biologic properties are due to an extensive network of cross-linked collagen fibers.¹³ Figure 41-12 illustrates how collagen cross-links from cartilage. The function of articular cartilage is to reduce friction in the joint and to distribute the forces of weightbearing. Articular cartilage is composed of chondrocytes (cartilage cells) (making up about 2% of the tissue) and an intercellular matrix made up of collagen (making up about 10% to 30% of weight), protein polysaccharides (making up 5% to 10% of weight), and water. The water content ranges from 60% to almost 80% of the net weight of the cartilage, and individual molecules rapidly enter or exit the articular cartilage to contribute to the resiliency of the tissue.

The intercellular matrix is produced by the chondrocytes, which synthesize and extrude collagen that, like the collagen produced by bone cells, is distributed throughout the cartilage in a highly organized system of fibers. Collagen fibers in cartilage are made up of many fine fibrils that, like bone fibrils, are assembled in an orderly fashion that makes them resistant to physical, metabolic, or chemical breakdown. The main differences between bone collagen and cartilage collagen are the amino acid content of the α-chains and the composition of the fibrils. Bone collagen fibrils are made up of two type I chains and one type II chain. Approximately 90% of the cartilage collagen fibrils is made up of three identical type II chains, with the remaining 10% made up of types V, VI, IX, X, and XI.

At the surface of articular cartilage, the collagen fibers run parallel to the joint surface and are closely compacted into a dense, protective mat. (Loss of this dense, compacted configuration at the surface subjects the underlying fibers to splitting and thinning, in which case the cartilage is unable to tolerate weightbearing.) In the middle layer (the proliferative zone) of the cartilage, the fibers are arranged tangential to the surface, which allows them to deform and absorb some of the force of weightbearing. In the bottom layer (the hypertrophic zone) of the cartilage, the fibers are perpendicular to the joint surface, allowing them to resist shear forces, and are embedded in a calcified layer of cartilage called the tidemark. The tidemark anchors the collagen fibers to the underlying (subchondral) bone and represents the zone between calcified and uncalcified cartilage. Collagen fibers are important components of the cartilage matrix because they account for approximately 60% of the dry weight and because they (1) anchor the cartilage securely to underlying bone, (2) provide a taut framework for the cartilage, (3) control the loss of fluid from the cartilage, and (4) prevent the escape of protein polysaccharides (proteoglycans) from the cartilage.

The proteoglycans are macromolecules consisting of proteins, carbohydrates (glycosaminoglycans), and hyaluronic acid. The glycosaminoglycans (keratan sulfate and chondroitin sulfate) are attached to the protein core, and several protein cores (with their attached glycosaminoglycans) are bound to a hyaluronic acid chain by a special protein called link protein. The proteoglycans give articular cartilage its stiff quality and regulate the movement of synovial fluid through the cartilage. Without proteoglycans, normal weightbearing would rapidly and completely press all the synovial fluid out of the cartilage. The proteoglycans act as a pump, permitting enough fluid to be pressed out to ensure that a fluid film is always present on the surface of the cartilage, even after hours of weightbearing. The pumping action of proteoglycans also draws synovial fluid back into the cartilage after a weightbearing load is released. Mobility and weightbearing are necessary for the pumping action of proteoglycans to occur. Nonuse of a joint quickly reduces the pumping action, which changes the composition of the matrix and interferes with the nutrition of the chondrocytes.

Articular cartilage has no blood vessels, lymph vessels, or nerves. Therefore, it is insensitive to pain and regenerates slowly and minimally after injury. Regeneration occurs primarily at sites where the articular cartilage meets the synovial membrane, where blood vessels and nutrients are available. In general, it has been difficult to enhance cartilage repair, but that may be changing (see What’s New? Progress in Rebuilding Cartilage).

Sensory Receptors: Although muscles function as effector organs, they also contain sensory receptors and are involved in sending different signals to the central nervous system. Among these are the muscle spindles and Golgi tendon organs. Spindles are mechanoreceptors that lie parallel to muscle fibers and respond to muscle stretching. Golgi tendon organs are dendrites that terminate and branch to tendons near the neuromuscular junction. Motor and sensory neurons secrete a proteoglycan called neuroregulin (NRG) that increases acetylcholine receptors and helps in the formation of muscle spindle fibers.¹⁴ The muscle spindles, Golgi tendon organs, and free nerve endings provide a means of reporting changes in length, tension, velocity, and tone in the muscle. This system of afferent signals is responsible for the muscle stretch response and maintenance of normal muscle tone.

Muscle Fibers: Each muscle fiber is a single muscle cell. This long cell is cylindrical and surrounded by a membrane capable of excitation and impulse propagation. The muscle fiber contains bundles of myofibrils, the fiber’s functional subunits, in a parallel arrangement along the longitudinal axis of the muscle (Figure 41-18). At birth the muscle fibers have completed development from precursor cells called myoblasts. All voluntary muscles are derived from the mesodermal layer of the embryo.

The type of peripheral nerve influences the muscle fiber and motor unit considerably. Whether motor nerves are fast or slow determines the type of muscle fibers in the motor unit. Type II fibers, also called white fast-motor fibers, are innervated by relatively large type II alpha motor neurons with fast conduction velocities. These fibers rely on a short-term anaerobic glycolytic system for rapid energy transfer, whereas type I fibers depend on aerobic oxidative metabolism. Histochemical stains are now routinely used to describe the structure of muscle fibers and contractile elements of muscle biopsy specimens. White muscle (type II fibers) stains dark in the enzyme stain adenosine triphosphatase (ATPase) at a pH of 9.4. Red muscle (type I fibers) appears lightly stained.

The overlap of muscle fibers that appear with staining gives the checkerboard appearance of muscle biopsy specimens and provides an equal distribution of fiber types throughout the muscle. This overlap also helps compensate for muscle fiber loss and fatigue of individual motor units during activity. In spite of this, some muscles contain proportionally more of one fiber type than another. The postural muscles have more type I fibers, allowing them the high resistance to fatigue that is necessary to maintain the same position for extended periods. The ocular muscles have more type II muscle fibers, allowing them to respond rapidly to visual changes. (Table 41-6 describes the specific characteristics of type I and type II fibers.)

The number of muscle fibers varies according to location. Large muscles, such as the gastrocnemius, have more fibers (1,200,000) than the smaller muscles, such as the lumbrical muscles in the hand (10,000). The diameter of muscle fibers also varies. The closely packed polygons are small (10 to 20 μm) until puberty, when they attain the normal adult diameter of 40 to 80 μm. Women usually have smaller-diameter fibers than men. Small muscles, such as the ocular muscles, are 15 μm in diameter; larger, more proximal muscles are 40 μm. Fiber size can have functional significance. Studies have shown that larger fiber diameter is associated with generation of greater forces. Fiber diameter can be increased by activities that cause hypertrophied muscle, such as exercise or occupational overuse.

The major components of the muscle fiber include the muscle membrane, myofibrils, sarcotubular system, sarcoplasm, and mitochondria (see Figure 41-18). The muscle membrane is a two-part membrane. It includes the sarcolemma, which contains the plasma membrane of the muscle cell, and the cell’s basement membrane. The sarcolemma is 7.5 nm thick and is capable of propagating electrical impulses to initiate contraction. At the motor nerve end plate, where the nerve impulse is transmitted, the sarcolemma forms the highly convoluted synaptic cleft. The sarcolemma is made up of lipid molecules and protein systems. The protein systems perform special functions, such as transport of nutrients and protein synthesis. They also provide the sodium-potassium pump and include the cell’s cholinergic receptor. The basement membrane is 50 nm thick and is composed primarily of proteins and polysaccharides. It serves as the cell’s microskeleton and maintains the shape of the muscle cell. The basement membrane also may function in some way to restrict further diffusion of electrolytes once they have crossed the sarcolemma.

The sarcoplasm is the cytoplasm of the muscle cell and contains the intracellular components that are common to all cells (see Chapter 1). The sarcoplasm is an aqueous substance that provides a matrix that surrounds the myofibrils. It contains numerous enzymes and proteins that are responsible for the cell’s energy production, protein synthesis, and oxygen storage. The mitochondria house enzyme systems for energy production, particularly those that regulate such processes as the citric acid cycle and adenosine triphosphate (ATP) formation. Many other structures are present in the sarcoplasm. The ribosomes are composed primarily of ribonucleic acid (RNA) and participate in the process of protein synthesis. The cell nucleus, satellite cells, glycogen granules, and lipid droplets are suspended in the sarcoplasmic matrix. Blood vessels, nerve endings, muscle spindles, and Golgi tendon organs are also directly located within this structure.

Unique to the muscle is the sarcotubular system, a network that includes the transverse tubules and the sarcoplasmic reticulum, which crosses the interior of the cell. The sarcoplasmic reticulum is made in the same manner as the endoplasmic reticulum in other cells. In the muscle cells the sarcoplasmic reticulum is involved in calcium transport, which initiates muscle contraction at the sarcomere, a portion of the myofibril. The sarcoplasmic reticulum is composed of tubules that run parallel to the myofibrils. The longitudinal tubules are termed sarcotubules. The transverse tubules, which are closely associated with the sarcotubules, run across the sarcoplasm and communicate with the extracellular space. Together, the tubules of this membrane system allow for intracellular calcium uptake, regulation, release during muscle contraction, and storage of calcium during muscle relaxation.