Basic Organization of Musculoskeletal Connective Tissues

With the exception of skeletal muscle, the tissues that make up the musculoskeletal system are generally classified as dense connective tissues. Connective tissues are composed of tissue-specific mesenchymal cells distributed throughout a specialized extracellular matrix (ECM). Dense connective tissues consist predominantly of ECM and contain relatively few cells. The ECM contains an array of structural fibers made up of cross-linked fibrillar proteins, along with a hydrated gelatinous interfibrillar matrix containing a variety of nonfibrillar proteins, proteoglycans (PGs), glycoproteins, proteolipids, and polysaccharides. The composition and molecular organization of the ECM define the mechanical properties and functionality of a given tissue. These properties vary greatly among tissues, reflecting the diverse functional roles to which different structures are adapted.

Cellular Components of Musculoskeletal Tissues

Musculoskeletal tissues contain a variety of cell types. The tissue-specific cells within musculo­skeletal structures are named in accordance with the tissues they inhabit (tenocytes within tendon, chondrocytes within cartilage, etc.). The majority of these are fully differentiated cells that are responsible for the synthesis and life-long turnover of the ECM that surrounds them. All connective tissues also contain small numbers of progenitor cells that represent variable stages of lineage commitment from multipotent mesenchymal stem cells to tissue-specific blasts forms (osteoblasts, tenoblasts, etc.). Progenitor cells play important roles in repair, regeneration, and adaptive remodeling of connective tissues.

With the exception of articular chondrocytes, musculoskeletal tissue cells are highly interconnected through adherens and gap junctions (Chi et al., 2005; Civitelli, 2008). These interconnections are established during development and allow close intercellular communication. The broad connectivity of the cellular network enhances the ability of tissues to mount regional responses to specific biological or mechanical stimuli (Ko & McCulloch, 2001; Wall & Banes, 2005). Connective tissue cells are also highly responsive to mechanical stimuli. Mechanotransduction is the process by which cells mount biological responses to mechanical stimuli (Ramage et al., 2009). The mechanical stresses imposed upon musculoskeletal tissues are borne primarily by the ECM. The resulting strains within the ECM may trigger cellular responses through a variety of mechanisms, including direct deformation of the plasma membrane and alteration of transmembrane ion conductance, deflection of the primary cilium, activation of cell-surface receptors by extracellular fluid shears, or ligand-independent activation of signaling receptors (Silver & Siperko, 2003; Bonewald, 2006). The response of a tissue to a mechanical stimulus may be either physiologic or pathologic, depending on the state of the tissue and the nature of the stimulus. Physiologic responses result in appropriate adaptive changes of the ECM that enhance a tissue’s ability to meet the demands placed upon it. An example of adaptive remodeling is the hypertrophy and mitochondrial biogenesis that occurs within skeletal muscle in response to athletic conditioning.

Molecular Components of Extracellular Matrix

Collagen

Collagen is the most abundant protein in the body, and is a ubiquitous component of all connective tissues. All collagens are triple helical proteins made up of three individual polypeptides called alpha chains. Homotypic collagens are composed of three identical alpha chains. Heterotypic collagens are composed of various combinations of alpha chains that differ in amino acid sequence. In mammals, there are 34 known alpha chain genes and at least 28 distinct collagen types. Use of alternative transcription start sites as well as alternative splicing of individual alpha chain transcripts results in a wide variety of collagen configurations with diverse structures and unique mechanical properties (Hulmes, 2002).

Collagens may be divided into several major groups: the fibrillar collagens are of primary im­­portance in the musculoskeletal system as they are the major structural components of connective tissues such as tendon, ligament, cartilage, and bone. The major fibrillar collagens are types I, II, and III. Type I collagen forms linear and extensively cross-linked macromolecular structures that impart high tensile strength to tendons and ligaments. It is also the most abundant collagen type in bone. Type II collagen is the predominant collagen in hyaline cartilage. Within articular cartilage, type II collagen fibrils are cross-linked into extensive three-dimensional (3-D) networks that provide resistance to deformation in a multitude of directions. Other collagen groups include the fibril-associated collagens with interrupted triple helices (FACIT collagens, types IX, XII, XIV, XVI, XIX, XX, XXI, and XXII), filamentous collagens (type VI), short-chain collagens (types VIII and X), and basement membrane collagens (types IV, VII, XV, and XVIII). Nonfibrillar collagens do not assemble into discrete fibrils; however, many associate with fibrillar collagens and regulate fibril assembly, fibril diameter, and interfibrillar interactions (FACIT collagens) (Kadler et al., 1996; Zhang et al., 2005). Others contribute to the unique mechanical properties of specific tissues (filamentous and basement membrane collagens).

Biosynthesis of collagen involves transcription and translation of the alpha chain gene, and production of a pre-pro-collagen peptide. During translation, specific proline and lysine residues within this molecule are hydroxylated by ascorbic acid- and iron-dependent prolyl and lysyl hy­­droxylases. Hydroxylated pre-pro-alpha chains undergo intracellular self-assembly into triple helical procollagen. The globular amino- and carboxy-termini of the procollagen molecules are subsequently cleaved by various metalloproteinases resulting in the formation of tropocollagen. Tropocollagen molecules are secreted from the cell where they assemble into a variety of higher order structures according to specific tissue requirements. Extracellular tropocollagen molecules are further stabilized by intermolecular cross-links as well as noncovalent association with other ECM components.

Within the ECM, fibrillar tropocollagen molecules further assemble in a staggered fashion into nascent fibrils. These fibrils are stabilized by intermolecular cross-links catalyzed by lysyl-oxidase enzymes. Numerous nonfibrillar collagens, other proteins, PGs, and proteolipids associate closely with the surfaces of collagen fibrils and regulate interfibrillar cohesion and interactions (Chapman, 1989). Groups of fibrils are further organized in hierarchical fashion into fascicles, which are themselves further bundled into fibers (Figure 3.1). Collagen fibers are the basic macroscopic structural units of many musculoskeletal structures such as tendons and ligaments.

Figure 3.1 Schematic depiction of the hierarchical structure of collagen fibers in tendon and ligament.

Elastin

Elastin is an important component of many musculoskeletal tissues, including tendons, ligaments, myofascial structures, joint capsule, and articular cartilage. Elastin provides tissues with elasticity, which refers to the ability of a tissue to undergo reversible deformation. The content of elastin within musculoskeletal tissues varies greatly depending on the requirement for elasticity. Elastin is a minor component of bone where it occurs predominantly with the walls of blood vessels; however, it is particularly abundant within the ECM of structures that undergo repeated cycles of elongation and elastic recoil such as joint capsules or the nuchal ligament.

Elastin is a high molecular weight insoluble protein biopolymer made up of numerous tro­poelastin subunits (Mithieux & Weiss, 2005). Tropoelastin is a 65 kDa hydrophobic protein. Biosynthesis of elastin involves transcription and translation of a single tropoelastin gene. Tropo­elastin is secreted from the cell as a complex with specific elastin-binding proteins. Within the ex­­tracellular environment, tropoelastin undergoes temperature-dependent conformational changes that expose hydrophobic residues within the molecule that allow its incorporation into a developing elastin macromolecule through hydrophobic interactions (Indik et al., 1989; Vrhovski & Weiss, 1998). This process is facilitated by many ECM components, most notably the glycoproteins fibrillin and fibronectin. Following assembly, elastin polymers are stabilized by covalent intermolecular cross-links, the formation of which is catalyzed by various copper-dependent lysyl oxidases. Groups of elastin polymers are further assembled in hierarchical fashion into higher order fibers that consist of a central core of cross-linked elastin surrounded by an organized coat of microfibrillar glycoproteins rich in fibrillin.

Elastic fibers are highly extensible and can withstand up to 200% increases in length from the resting state. Elastic fibers are also extremely durable, and are capable of virtually unlimited numbers of cycles of elongation and elastic recoil without loss of strength (Keeley et al., 2002). Production of elastin (elastogenesis) is prominent during growth, as well as during the repair and remodeling phases of tissue healing. However, once formed, elastic fibers are extraordinarily stable and may persist throughout adulthood without turnover.

Proteoglycans

Proteoglycans (PGs) are glycosylated proteins that are prominent components of the ECM of all connective tissues. The basic structure of a PG consists of a core protein to which a variable number of glycosaminoglycan (GAG) side chains are covalently attached (Figure 3.2). Core proteins vary greatly in length and amino acid sequence. The GAG side chains are long, linear polysaccharide polymers composed of repeating disaccharide units. The disaccharide units are composed of two 6-carbon sugars, the first of which is either a hexose or a hexuronic acid, and the second of which is an amino sugar (hexosamine) (Table 3.1). The sugars within most GAGs are sulfated, which renders the polysaccharide chains highly negatively charged. GAGs are covalently linked to serine residues within a core protein. Hyaluronic acid (HA), a ubiquitous component of ECMs throughout the body, is unique within the family of GAGs since it is neither sulfated nor covalently linked to proteins.

Figure 3.2 Aggrecan structure. Multiple proteoglycan monomers are bound by specific link proteins to a backbone of hyaluronic acid to form macromolecular aggregating proteoglycans.

Table 3.1 Chemical composition of major glycosaminoglycans

Several classes of PGs are recognized, the most thoroughly characterized of which are the interstitial PGs. This class includes the aggregating PGs and the small leucine-rich PGs (SLRPs) (Hardingham & Fosang, 1992). The aggregating PGs include aggrecan, versican, brevican, and neurocan. These PG species are massive macromolecular complexes in which many individual PG molecules are assembled in a brush-like array along a backbone of HA (Figure 3.2). Due to their extremely negative charge, aggregating PGs have a high affinity for water. Aggregating PGs are immobilized within a given tissue through association with collagen fibrils. Their high degree of hydration underlies the turgidity and resistance to compression of several musculoskeletal tissues such as hyaline articular cartilage, meniscal fibrocartilage, and the nucleus pulposus of the intervertebral disk.

The SLRPs are a structurally diverse group of PGs with variable degrees of GAG conjugation and that are expressed in tissue-specific patterns. SLRPs associate with fibrillar elements of the ECM such as collagen and elastin and have many functions, including modulation of the assembly and interaction of collagen and elastin fibers, modulation of ion transport through the ECM, and regulation of growth factor effects on connective tissue cells (Schaefer & Iozzo, 2008).

PG synthesis involves transcription and translation of a core protein, GAG conjugation of the protein, and secretion of mature PG into the extracellular environment. In comparison to the fibrillar components of the ECM, PGs undergo rapid turnover. Existing PGs are degraded by a variety of proteases and polysaccharidases. In turn, PG biosynthesis is a highly regulated anabolic process that can be triggered by exposure of cells to a variety of biological mediators as well as some pharmacological agents. The ability to alter the types and concentrations of PGs within the ECM in response to specific stimuli allows resident cells to adjust many properties of the ECM in accordance with tissue demand. PG turnover thus represents an important mechanism of tissue adaptation, and targeted stimulation of PG production in vivo is an area of great clinical therapeutic interest.

Musculoskeletal Ontogeny

Regeneration is the reestablishment of the original form and function of a tissue after injury or loss. Within the musculoskeletal system, bone and muscle are capable of regeneration, while the healing of tendon, ligament, and cartilage results in mechanically inferior tissues. Currently, there is great interest in clinical strategies, including rehabilitative programs, designed to promote or accelerate regenerative healing (Ambrosio et al., 2010). Tissue regeneration often involves a close recapitulation of developmental morphogenesis; thus, an understanding of basic developmental processes is relevant to physical rehabilitation. A thorough review of musculoskeletal development is beyond the scope of this chapter; however, several key concepts are outlined as they relate to rehabilitation, especially of the canine athlete.

The mammalian musculoskeletal system derives predominantly from mesoderm. During development, mesoderm is established during gastrulation, as cells of the deep surface of the epiblast delaminate from the ectodermal portion of the primitive streak to populate the mesenchyme between the ectodermal and endodermal germ layers. During neurulation, these cells organize along the lateral aspects of the developing neural tube to form the paraxial mesoderm. Secretion of morphogens by cells of the neural tube and adjacent ectoderm triggers segmentation of the par­axial mesoderm into somites. The ventromedial aspect of the somite forms the sclerotome, from which vertebrae and ribs derive. The dorsolateral aspect of the somite forms the dermomyotome, which further organizes into superficial dermotomal and deep myotomal components. The cells of the myotome undergo myoblastic differentiation and give rise to the axial musculature. The lateral aspect of the paraxial mesoderm develops into the lateral plate mesoderm, which divides into superficial somatic and deep splanchnic layers (Figure 3.3). The limbs originate as focal thickenings of the somatic lateral plate mesoderm (limb buds). The early limb bud is populated by myoblastic cells that migrate into the lateral plate mesoderm from the somitic myotomes, and that ultimately give rise to the appendicular musculature. Outgrowths of cells of the neural tube enter the limb bud in conjunction with myoblasts to innervate developing limb structures. Outward growth and patterning of the limb is guided by gradients of signaling molecules produced by the surrounding ectoderm.

Figure 3.3 Schematic cross-sectional depiction of embryologic origins of musculoskeletal structure. A. Segmentation of paraxial mesoderm adjacent to the neural tube (N) and notochord (NC) leads to the formation of somites (S) and lateral plate mesoderm (LPM). B. Each somite segregates into a ventromedial sclerotome (SC) and a dorsolateral dermomyotome (DM). C. The dermomyotome separates into a dorsolateral dermatome (red) and a ventromedial myotome (blue). Appendicular musculoskeletal structures derive from mesodermal precursors that migrate into the limb bud (LB) from the ventrolateral dermomyotome and lateral plate mesoderm (arrows). Axial musculoskeletal structures derive from the sclerotome. Dermatome (DT). Myotome (MT).

Myoblastic differentiation within the myotome is the earliest musculoskeletal fate specification to occur during development. Muscle development is triggered by the activation of a myogenic transcriptional program that culminates in the expression of a core set of myogenic factors, including myogenic factor 5 (MYF5), muscle-specific regulatory factor-4 (MRF-4), myoblast determination protein (MYOD), and myogenin (Pownall et al., 2002). The timing and sequence of expression of these myogenic factors varies with anatomical site during development. Contractile myofibers first appear in the limbs at approximately mid-gestation, prior to limb innervation. These primary fibers persist as type I (slow-twitch or oxidative) fibers in the adult. Secondary myofibers develop later concomitant with the establishment of limb innervation and become type II (fast-twitch or glycolytic) fibers. Muscle contractility is robust throughout the latter half of gestation, and the mechanical forces produced by developing muscle are essential to the appropriate development of all other musculoskeletal structures.

With the exception of the craniofacial skeleton that is largely of neural crest origin, bones originate as condensations of mesenchymal cells that initially differentiate into chondrocytes to form a cartilaginous model of the developing skeleton. As the chondrocytes undergo interstitial growth, hypoxia develops within the central region of the avascular cartilaginous precursor. This triggers hypertrophy of chondrocytes, and stimulates production of angiogenic growth factors and vascular invasion of the cartilage model. Vascularization marks the onset of endochondral ossification as the cartilage model becomes populated with osteoprogenitors and as chondroid matrix is resorbed and replaced with osteoid. Endochondral ossification continues throughout postnatal growth, primarily within the physes of the long bones. This process of developmental endochondral ossification is recapitulated with remarkable fidelity during indirect fracture healing (see below).

The initial mesenchymal condensation that precedes appendicular bone formation is initially continuous along the length of the elongating limb bud. As chondrogenic differentiation occurs, this mesenchymal column undergoes a process of segmentation marked by the appearance of discrete interzones that mark the sites of future diarthrodial joints. Apoptosis of cells within the interzone leads to the formation of a fluid-filled joint space, a process termed cavitation (Khan et al., 2007). Wnt14 is a key morphogen expressed at these interzones (Archer et al., 2003). Separation of the articular surfaces and development of a fully mobile synovial joint requires continuous mobilization of the nascent joint by contraction of associated developing musculature, as well as distention of the joint cavity with HA. The HA within the interzone is initially secreted by cells of the articular surfaces and later by the developing synovium. Mechanical strain of joint tissues stimulates production of HA through upregulation of some isoforms of HA synthase, an effect that persists through adulthood (Itano & Kimata, 2002; Momberger et al., 2005).

Tendon and ligament primordia arise as condensations of mesenchymal cells that initially reside immediately subjacent to the basal lamina of the developing dermis (Benjamin & Ralphs, 1995). These cells initially organize into parallel longitudinal rows and subsequently become separated as they elaborate collagen-rich ECM. During differentiation, they develop long cytoplasmic processes by which cell-to-cell contact is maintained despite deposition of large quantities of intercellular ECM. The bony prominences that form attachment sites for tendons and ligaments are defined during formation of the cartilaginous anlage of a bone; however, full maturation of both the bony tuberosities at which tendons and ligaments insert, as well as their enthesial architecture, is dependent upon traction forces exerted on these sites by developing muscles. In the proximal portion of the limbs, connections with bone are established during the early stages of tendon differentiation. In contrast, distal tendons initially lack connection with bone but establish insertions later in development through fusion with enthesial outgrowths of a target bone.

During development, all musculoskeletal tissues are populated with small but significant numbers of undifferentiated progenitor cells or mesenchymal stem cells (Figure 3.4). These cells include osteoblasts of bone, satellite cells of skeletal muscle, and stem cells of tendon, ligament, and cartilage. Mesenchymal stem cells are multipotent, capable of undergoing osteogenic, chondrogenic, adipogenic, or neurogenic differentiation in response to appropriate signals. They also are capable of self-renewal through asymmetric cell division. They are activated by injury or conditioning stimuli, and play important roles in the healing and functional adaptation of tissues (Wu et al., 2007; Fan et al., 2009; Tapp et al., 2009; Lim et al., 2010; Reich et al., 2012). Stem cell therapy involving harvest and orthotopic implantation of autologous mesenchymal stem cells is an area of active orthopedic research and has become an accepted treatment for progressive osteoarthrosis in the dog (Black et al., 2007, 2008; Guercio et al., 2012).

Figure 3.4 Canine bone marrow-derived mesenchymal stem cells in primary culture show characteristic mesenchymal morphology. These cells are capable of chondrogenic, osteogenic, adipogenic, or neurogenic differentiation in response to specific signals.

Structure–Function Relationships of Musculoskeletal Tissues

Basic Concepts

The tissues of the musculoskeletal system are highly responsive to mechanical strains. From a biomechanical perspective, physiologic adaptation refers to the process by which musculoskeletal tissues adjust their biochemical composition, molecular architecture, and mechanical properties in accordance with the demands placed upon them. Both athletic training and rehabilitative therapy involve the application of controlled forces to the musculoskeletal system to facilitate physiologic adaptations that are specifically suited to a given athletic or therapeutic objective. Here we introduce several basic concepts related to the mechanical properties and functional adaptations of musculoskeletal tissues.

The body is subject to two basic categories of force. Intrinsic forces originate from within the body due to muscular contractions or the inherent elasticity of connective tissues such as ligaments or myofasciae. Extrinsic forces arise from outside the body and include ground reaction forces due to gravity as well as forces imposed on the body through contact with other objects.

When subjected to force, objects deform. This relationship can be represented graphically as a force-deformation curve, which describes the structural properties of a given object. When normalized to the cross-sectional area of an object, the applied force and resulting deformation are referred to as stress and strain, respectively. Stress–strain relationships thus describe the mechanical properties of a particular material. An idealized stress–strain curve pertaining to musculoskeletal tissues is illustrated in (Figure 3.5). The initial nonlinear portion of the curve is the toe region and represents an early phase of deformation that occurs as stress is first applied to the material. In connective tissues, the toe region typically reflects the straightening of crimped collagen fibrils or the elongation of elastin fibers. The linear portion of the curve represents a zone of elastic deformation, where the material will return to its original state upon removal of the applied stress. The slope of this region of the curve is called the modulus, and describes the stiffness of the material. The yield point represents the transition from elastic to plastic deformation; beyond the yield point, structural alterations within the material prevent it from returning to its original state despite removal of the applied stress. The failure point represents complete loss of structural integrity and macroscopic breakdown of the material such as would occur with bone fracture or tendon rupture. The area under the curve represents the total amount of energy introduced into the material to cause failure. The maximum strength of the material is indicated by mu, the level of applied stress at the point of failure.

Figure 3.5 Idealized stress–strain curve highlighting key mechanical parameters of musculoskeletal tissues. The slope of the linear region describes the stiffness (modulus) of the material. The area under the curve (shaded region) represents the total energy introduced into the material to cause mechanical failure.

Musculoskeletal tissues are anisotropic and viscoelastic. Mechanical properties of anisotropic materials vary depending upon the direction of applied stress. For example, tendons are capable of resisting high tensile loads, but deform readily when subjected to compressive stress. Mechanical properties of viscoelastic materials vary depending upon the rate at which stress is applied. Viscoelasticity is a melding of the basic properties of viscosity and elasticity. Viscosity is a property of fluids that reflects the resistance of molecules to strain (flow) in response to a given force. Highly viscous fluids are resistant to flow, but will do so linearly and irreversibly over time in response to a constant force. Elasticity is a property of solids that deform instantly in response to an applied stress but that return to their original state following removal of the stress. Viscoelastic materials demonstrate elastic deformation in response to rapid loading but undergo permanent change of shape in re­­sponse to sustained stress. The progressive strain that occurs in viscoelastic materials in response to a constant stress is called creep. Stress relaxation is a related property that refers to the gradual dissipation of internal stress that occurs in response to a constant strain.

The viscoelasticity of musculoskeletal tissues derives from their composite structure: within the ECM, collagen and elastin fibrils form the solid component and impart tensile resistance and elasticity, while the hydrated PG-rich extrafibrillar matrix behaves as a viscous fluid that allows gradual interfibrillar shear and permanent strain in response to sustained stress (Elliott et al., 2003). Under normal conditions, the responses of musculoskeletal tissues to physiologic stresses are primarily elastic. Strains experienced by the ECM are nevertheless sensed by resident cell populations and trigger constitutive ECM remodeling activity by which the structural integrity of a given tissue is maintained (Kjaer, 2004). In tissues such as muscle, tendon, and ligament, sustained or high-intensity activity, such as occurs during athletic training or performance, may cause greater degrees of plastic deformation of the ECM. This type of strain represents a form of ECM microinjury (Kjaer, 2004; Mackey et al., 2008). Mild inflammatory responses may occur in vascularized tissues in response to stress-induced plastic deformations of the ECM. Inflammatory mediators may in turn trigger anabolic cellular responses that result in adaptive changes in ECM composition and a net gain in tissue strength (Vierck et al., 2000). This type of cellular response underlies the physiologic adaptation of musculoskeletal tissues and is the basis for athletic conditioning.

Skeletal Muscle

Organization and Motor Activity

Collectively, the skeletal musculature is the largest organ in the body. Skeletal muscle is a complex and highly organized tissue composed of repeating units called sarcomeres. Individual muscles are organized into beds containing numerous fascicles surrounded by perimysium, and each fascicle is composed of multinucleated myofibers enclosed by an endomysium (Figure 3.6). The epimysium is the collagen-rich sheath that surrounds a whole muscle; epimysium is continuous with the dense aponeurotic fascial sheets that enclose some muscle groups. The perimysium is the primary component of the ECM through which the force of contrac­­tion is transferred from a muscle to its associated tendon.

Figure 3.6 Hierarchical organization of skeletal muscle.

Reproduced by permission of Toll et al. (2010).

Single myofibers act in concert through the sliding filament model of actin and myosin within organized sarcomeres (Figure 3.7). Within the sarcomere, structural proteins anchor actin, troponins, and tropomyosin to the Z-line that contains actinin. Multimeric myosin proteins are suspended as in­­tercalating filamentous strands with globular head units that function as ratchets along adjacent actin filaments. Binding of acetylcholine to receptors on the surface of the myofiber sets off a cascade of intracellular signaling events resulting in calcium release from the sarcoplasmic reticulum. Intracellular free calcium interacts with troponin C which is bound to the actin, troponin complex (I, C, and T), and tropomyosin (Figure 3.8). This interaction drives a conformational change in the tropomyosin, allowing exposure of a groove that allows myosin heads to interact with the actin filament. This interaction causes the adenosine triphosphate (ATP) bound to the myosin head interacting with the actin to undergo hydrolysis (Moczydlowski & Apkon, 2009). Adenosine diphosphate (ADP) is then released from the myosin head, allowing a conformational shift in the myosin head from an open to a closed position leading to a shortening of the myofiber. Muscle contraction is dependent upon ATP hydrolysis, and generation of ATP is a key rate-limiting step in muscle contractility. This is discussed in more detail in Chapter 4.

Figure 3.7 Contraction of skeletal muscle occurs due to ATP-dependent conformational changes of the globular heads of myosin proteins that cause myosin to slide along adjacent actin filaments.

Reproduced by permission of Toll et al. (2010).

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