Structure and Function of the Musculoskeletal System

Originating from MSCs, osteoblasts are the primary bone-producing cells and are involved in many functions related to the skeletal system (see Table 43.1). Mature osteoblasts produce inorganic calcium phosphate, which is converted to hydroxyapatite, and an organic matrix that is composed mainly of type I collagen.⁴

Once this process is complete, osteoblasts deposit new bone in response to the bone resorbed by osteoclasts.⁴ Osteoblasts are responsive to parathyroid hormone (PTH) and produce osteocalcin when stimulated by 1,25-dihydroxy-vitamin D₃. Osteoblasts are active on the outer surfaces of bones, where they form a single layer of cells. Osteoblasts initiate new bone formation by their synthesis of osteoid (nonmineralized bone matrix). Osteoblasts also mineralize the newly formed bone matrix. Stimulation of new bone formation and orderly mineralization of bone matrix occur 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. Enzymes, signaling proteins, and growth factors, including BMPs and other members of the TGF-β superfamily, are critical components of bone formation, maintenance, and remodeling (see Table 43.2).

Osteocytes, the most abundant cells in bone, are transformed osteoblasts trapped or surrounded in osteoid as it hardens because of minerals that enter during calcification (see Fig. 43.2B). It is the final differentiation stage for an osteoblast. The osteocyte is within a space in the hardened bone matrix called a lacuna. Osteocytes have numerous functions, including acting as mechanoreceptors and synthesizing certain matrix molecules, playing a major role in controlling osteoblast differentiation and production of growth factors, and maintaining bone homeostasis.

As the major source of sclerostin, receptor activator nuclear factor κ-B ligand (RANKL), and osteoprotegerin, osteocytes are thought to be key regulators of both bone formation and bone resorption.⁵ They also help concentrate nutrients in the matrix. Osteocytes obtain nutrients from capillaries in the canaliculi, which contain nutrient-rich fluids. Through exchanges among these cells, hormone catalysts, and minerals, optimal levels of calcium, phosphorus, and other minerals are maintained in blood plasma.

One of the osteocyte’s primary functions is to act as a mechanoreceptor, responding to changes in weightbearing or other stressors (“loading”) on bone. Lying within the lacunae are the osteocyte’s primary cilia, which are likely the primary mechanoreceptors in bone. Once changes in bone, such as mechanical stress, hormonal imbalance, loading, or unloading, are detected by the osteocyte’s mechanoreceptors, multiple molecular signals are produced, and the process of bone remodeling begins. Remodeling is described in the Maintenance of Bone Integrity Section.

A specific area of the cell membrane forms adjacent to the bone surface and develops multiple infoldings to permit intimate contact with the resorption bay. These infoldings, known as the ruffled border, greatly increase the surface areas of cells under their scalloped or ruffled borders. Osteoclasts resorb bone by the secretion of hydrochloric acid, acid proteases (such as cathepsin K), and matrix metalloproteinases (MMPs) that help digest collagen, along with the action of cytokines (see Table 43.2). Osteoclasts also resorb bone through the action of lysosomes (digestive vacuoles) filled with hydrolytic enzymes in their mitochondria.

Osteoclasts bind to the bone surfaces through attachments called podosomes, which are footlike structures that cluster together along a sealing membrane that forms a “belt” containing multiple proteins, enzymes, and integrin receptors. Once resorption is complete, the osteoclasts retract and loosen from the bone surface under the ruffled border through the action of calcitonin. Calcitonin binds to receptor areas of the osteoclasts’ cell membranes to effectively loosen the osteoclasts from the bone surfaces. Once resorption is completed, osteoclasts disappear by the process of degeneration, either by reverting to the form of their parent cells or by undergoing cell movements away from the site, in which the osteoclast becomes an inactive or a resting osteoclast.

In addition to resorption of bone, osteoclasts assist the endocrine and renal systems in maintaining appropriate serum calcium and phosphorus levels. Osteoclasts also appear to have a role in the body's immune response.

Collagen fibers make up the bulk of the bone matrix. They are formed in this way:

Glycoproteins are carbohydrate-protein com-plexes that control the collagen interactions that lead to fibril formation. They also may function in calcification. Four glycoproteins are present in bone: sialoprotein, which binds easily with calcium; osteocalcin, which binds preferentially to crystallized calcium; bone albumin, which is identical to serum albumin and possibly transports essential nutrients to and from bone cells and maintains the osmotic pressure of bone fluid; and alpha-glycoprotein (α-glycoprotein), which probably plays a significant role in calcification and also may facilitate bone resorption by activating osteoclasts (see Table 43.1).

The synovial membrane (synovium) is a smooth, delicate inner lining of the joint capsule found in the nonarticular portion of the synovial joint and any ligaments or tendons that traverse this cavity (Fig. 43.8). It is composed of two layers: the vascular subintima and the thin cellular 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 cellular intima consists of rows of synovial cells embedded in a fiber-free intercellular matrix and contains two types of cells—A and B. A cells (macrophages) ingest and remove (phagocytose) bacteria and particles of debris in the joint cavity; B cells (fibroblasts) are the most numerous and secrete hyaluronate, which gives synovial fluid its viscous quality. The synovial membrane is richly supplied with blood and lymphatic vessels and is capable of rapid repair and regeneration.

An illustration depicts the layered structure of the synovium with labels indicating cartilage, chondrocyte, synovial fluid, compact zone, mast cell, capillary, small vessels, macrophage, subintima, fibroblast, venule, lymphatic vessels, and arteriole.

At the surface of articular cartilage, the collagen fibers run parallel to the joint surface and are closely compacted into a dense, protective mat. In the middle layer (the proliferative zone) of the cartilage, the fibers are arranged tangential to the surface, allowing them to deform and absorb some of the weightbearing (Fig. 43.9). 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. 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 give articular cartilage its stiff quality and regulate the movement of synovial fluid through the cartilage. The proteoglycans are macromolecules consisting of proteins, carbohydrates (glycosaminoglycans), and hyaluronic acid. 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. 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, changing the composition of the matrix and interfering with the nutrition of the chondrocytes. Normal articular cartilage has no blood vessels, lymph vessels, or nerves. Therefore, it is insensitive to pain and regenerates slowly and minimally after injury.⁶ 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 Emerging Science Box: Progress in Rebuilding Cartilage). Synovial joints are described as uniaxial, biaxial, or multiaxial according to the shapes of the bone ends and the type of movement occurring at the joint (Fig. 43.10). Usually, one of the bones is stable and serves as an axis for the motion of the other bone. The body movements made possible by various synovial joints are either circular or angular (Fig. 43.11).

Three illustrations depict the various movements of synovial joints. The first illustration depicts the uniaxial (elbow) movement of the synovial joint in the elbow which shows the sagittal plane of movement along the axis of rotation occurs. The second illustration depicts the biaxial (finger) movement of the synovial joint in the finger which shows the sagittal plane of movement along the transverse axis and the frontal plane of movement along the anterior or posterior axis. The third illustration depicts the multiaxial (hip) movement of the synovial joint in the hip which shows the sagittal plane of movement around the transverse axis, the frontal plane of movement along the anterior or posterior axis, and the transverse plane of movement along the longitudinal axis.

An illustration depicts the various types of body movements at synovial joints indicated by arrow marks. The body movements from top to bottom are as follows. Arm or hand involves circumduction, an extension of the elbow, supination, and adduction. The hip or leg involves abduction, hip and knee flexion, hyperextension, and extension. Head involves flexion or hyperflexion, rotation. Foot involves dorsiflexion, plantar flexion, and eversion, or inversion.

Each muscle fiber is a single muscle cell that is cylindrical in structure 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 (Fig. 43.15). 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. Genetic transcription factors, most notably MyoD, induce skeletal muscle differentiation. Myoblasts are the main cells responsible for muscle growth and regeneration. Myoblasts are termed satellite cells when in a dormant state. Satellite cells are crucial in muscle growth, maintenance, repair, and regeneration. Once muscle is injured, satellite cells become activated and increase the number of transcriptional factors necessary to form myoblasts and assist in repair.

An illustration depicts the cutaway section of muscle fiber with its major components labeled clockwise from the left. Sarcolemma, sarcoplasm, nucleus, sarcomere, myofibril, T-tubule, mitochondria, sarcoplasmic reticulum, triad, and myofilaments.

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. White muscle (type II fibers [white fast-twitch fibers]) is 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. Red muscle (type I fibers [slow-twitch fibers]) depends on aerobic oxidative metabolism. Table 43.4 describes the specific characteristics of type I and type II fibers.

The overlap of muscle fibers that appears with staining gives a checkerboard appearance to muscle biopsy specimens. This overlap provides an equal distribution of fiber types throughout the muscle and helps to compensate for muscle fiber loss and fatigue of individual motor units during activity. Despite this, some muscles contain proportionally more of one fiber type than another. 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.

The number of muscle fibers varies according to location. Large muscles, such as the gastrocnemius, have more fibers (1.2 million) than 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 in diameter. Fiber size can have functional significance, such as the association of larger fiber diameter with the generation of greater forces.

The major components of the muscle fiber include the muscle membrane, sarcoplasm, mitochondria, sarcotubular system, and myofibrils (see Fig. 43.15). 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 μm 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 μm thick and is composed primarily of proteins and polysaccharides. It also serves as the cell's microskeleton and maintains the shape of the muscle cell. The basement membrane also may function to restrict further diffusion of electrolytes once they have crossed the sarcolemma.

The sarcoplasm is the cytoplasm of the muscle cell and contains myoglobin plus the intracellular components that are common to all cells (see Chapter 1). Myoglobin is a protein found primarily in skeletal and heart muscle. Related to hemoglobin in the blood, myoglobin stores oxygen and iron in the muscle. 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 processes such as the citric acid cycle and adenosine triphosphate (ATP) formation. Many other structures are present in the sarcoplasm. The ribosomes are composed of primarily ribonucleic acid (RNA) and participate in 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 constructed like the endoplasmic reticulum in other cells. The sarcoplasmic reticulum is composed of tubules that run parallel to the myofibrils. The longitudinal tubules are termed sarcotubules. In muscle cells, the sarcoplasmic reticulum contains a network of intracellular receptors known as ryanodine receptors (RyRs). In response to a nerve impulse, RyR1 (found in skeletal muscle cells) releases intracellular calcium and initiates muscle contraction at the sarcomere, a portion of the myofibril. The transverse tubules, which also contain calcium release channels and 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 uptake and regulation of intracellular calcium, release of calcium during muscle contraction, and storage of calcium during muscle relaxation.

Myofibrils

Myofibrils, the most abundant subcellular muscle component (85% to 90% of the total volume), are the functional units of muscle contraction. Each myofibril contains sarcomeres, which appear at intervals (see Fig. 43.15). Sarcomeres are composed of several proteins. The two most abundant are actin and myosin, but three other giant, muscle-specific proteins (titin, nebulin, and obscurin) play important roles in myofibril formation and function (Table 43.5).

Table 43.5

Contractile Proteins of Skeletal Muscle Sarcomere

Protein	Location	Function
Actinin	Z disk	Attaches actin to Z disks; helps coordinate sarcomere contraction; cross-links thin filaments in adjacent sarcomeres
Actin	I band (thin filaments)	Contraction; activates myosin-ATPase; interacts with myosin
α-Actin	Z disk	Main ligand of titin; links and controls filament length
β-Actin	Z disk	Regulatory and structural function; links filaments, controls filament length
Myosin	A band (thick filament)	Contraction force; two distinct types: myosin heavy chain (MyHC) and myosin light chain (MyLC); hydrolyzes ATP and develops tension
Titina (largest and third most abundant muscle protein)	Half of sarcomere (from Z disk to M band)	Coordinates assembly of proteins that comprise sarcomere; regulates resting length of sarcomere; important for myofibril assembly, stabilization, and maintenance
Nebulina	I band (with α-actin)	Interacts with myosin to produce contraction; binding site for actin, desmin, titin, other proteins; stabilizes and regulates length of actin filaments; plays role in assembly, structure, and maintenance of Z disks
Obscurina	Surrounds sarcomere (mainly at Z disk and M band)	May mediate interaction of sarcoplasmic reticulum and myofibrils; plays role in muscle response to injury; has role in formation and stabilization of M bands and A band

ATP, Adenosine triphosphate; ATPase, adenosine triphosphatase.

^aAlso may function as molecular scaffolds for myofibril formation.

Data from Herzog JA, Leonard TR, Jinha A, et al. Titin (visco-) elasticity in skeletal muscle myofibrils. Molecular and Cellular Biomechanics, 2014;11(1):1–17; Luther PK. The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling. Journal of Muscle Research and Cell Motility, 2009;30:171–185; Pappas CT, Krieg PA, Gregorio CC. Nebulin regulates actin filament lengths by a stabilization mechanism. Journal of Cell Biology, 2010;189(5):858–870; Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiological Reviews, 2011;91:1447–1531.

On cross section, they are seen to be irregular polygons with a mean diameter of less than 1 μm. Each myofibril is composed of serially repeating sarcomeres, separated by Z bands, which give the muscle its striped, cross-striated appearance. Each sarcomere has a dark A band and is flanked by two light I bands (Fig. 43.16). The A band is 1.5 to 1.6 μm long and contains the thick myosin filaments. Included in the A band is a lighter zone called the H band, and in the center of the H band is the dark M band, or M line. The I band, which contains actin, is divided at the midpoint of each sarcomere by the Z band. Its length varies with the start of muscle contraction. The Z disk (made up of different layers of Z bands, depending on muscle type) marks the boundaries of the sarcomere.

Three illustrations depict the sarcomere of muscle fibers. Illustration A depicts the micrographic view of skeletal muscle sarcomere showing the Z-disk, M line, I band, H band, A band accompanied by the schematic representation of relaxed striated muscle fiber sarcomere showing the actin-based thin filaments, myosin-based thick filaments, and titin. Illustration B depicts the schematic representation of contracted muscle fiber sarcomere.

Myofibrils are composed of myofilaments. Each myofilament is structured in a closely packed hexagonal arrangement, with two thin filaments for every thick filament. The thick filament, along with C protein and M line protein, is made up of myosin. Myosin has two subunits—heavy and light meromyosin, which resemble twisted golf club shafts. The thin filaments are twisted double strands consisting of actin, troponin, and tropomyosin (see Chapter 31).