Muscle Dysfunction PDF

1048 SECTION II Pathology of Organ Systems t c A t ts B Figure 16.18 Tendon, Joint, Mouse. A, Gastrocnemius tendon (t). The tendon is composed of parallel arrays of closely packed collagen fibers and low numbers of fibroblast-like cells called tenocytes (see higher magnification in B; arrowheads). T...

1048 SECTION II Pathology of Organ Systems t c A t ts B Figure 16.18 Tendon, Joint, Mouse. A, Gastrocnemius tendon (t). The tendon is composed of parallel arrays of closely packed collagen fibers and low numbers of fibroblast-like cells called tenocytes (see higher magnification in B; arrowheads). The tendon is covered by flattened synoviocytes (see higher magnification in B), so it may glide smoothly over the synoviocytes of the tendon sheath. c, Calcaneus insertion. Hematoxylin and eosin (H&E) stain. B, Higher magnification of tendon sheath. The enveloping structure enclosing the tendon is the tendon sheath (ts), and it is lined by synoviocytes (arrows). t, Gastrocnemius tendon. H&E stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) basic structural unit of tendon. The collagen polypeptides form a triple helix, which self-assembles into collagen fibrils with intermolecular cross-links that form between adjacent helices. The collagen polypeptides and the ensuing triple helix are synthesized inside the cell, secreted into the extracellular matrix, and assembled into the microfibrillar units that constitute the collagen fibers. This step is promoted by a specialized enzyme called lysyl oxidase, which promotes cross-link formation—a process involving placement of stable cross-links within and between the molecules. Cross-link formation is the critical step that gives collagen fibers their strength. Tendon is stronger per unit area than muscle, and its tensile strength equals that of bone, although it is flexible and slightly extensible. The parallel arrangement of tendon collagen fibers resists tension so that contractile energy is not lost during transmission from muscle to bone. The mechanical properties of tendons depend on the collagen fiber diameter and orientation; however, the proteoglycan components of tendons also are important to the mechanical properties. Whereas the collagen fibrils allow tendons to resist tensile stress, the proteoglycans allow them to resist compressive stress. Skeletal ligaments are defined as dense bands of collagenous tissue that span a joint and then become anchored to the bone at either end. They vary in size, shape, orientation, and location. Their bony attachments are called insertions. Biochemically, ligaments are approximately two-thirds water and one-third solid. Type I collagen accounts for 85% of the collagen (other collagen types include III, V, VI, XI, and XIV), and the collagens account for approximately 75% of the dry weight, with the balance being made up by proteoglycans, elastin, and other proteins. While the ligament appears as a single structure, during joint movement some fibers appear to tighten or loosen depending on the bone positions and the forces that are applied, confirming the complexity of these structures. Histologically, ligaments are composed of fibroblasts that are surrounded by matrix. The fibroblasts are responsible for matrix synthesis and are relatively few in number, representing a small percentage of the total ligament volume. Recent studies have indicated that normal ligament cells may communicate by means of prominent cytoplasmic extensions that extend for long distances and connect to cytoplasmic extensions from adjacent cells, thus forming an elaborate three-dimensional architecture. Gap junctions have also been detected in association with these cell connections, raising the possibility of cell-to-cell communication and the potential to coordinate cellular and metabolic responses throughout the tissue. Ligament microstructure reveals collagen bundles aligned along the long axis of the ligament and displaying an underlying “waviness” or crimp along the length, similar to that present in tendon. Crimp is thought to play a biomechanical role, possibly relating to the ligament’s loading state with increased loading likely resulting in some areas of the ligament uncrimping, allowing the ligament to elongate without sustaining damage. One of the main functions of ligaments is mechanical because they passively stabilize joints and help guide those joints through their normal range of motion when a tensile load is applied. Another function of ligaments relates to their viscoelastic behavior in helping provide joint homeostasis. Ligaments “load relax,” which means that loads/stresses decrease within the ligament if they are pulled to constant deformations. A third function of ligaments is their role in joint proprioception. In joints such as the stifle, proprioception is provided principally by joint, muscle, and cutaneous receptors. When ligaments are strained, they invoke neurologic feedback signals that then activate muscular contraction, which appears to play a role in joint position sense. Tendons and ligaments attach to bone in a similar manner, through osteotendinous or osteoligamentous junctions, respectively. These junctions are known as entheses and are distinguished as fibrous and fibrocartilaginous according to the type of tissue present at the attachment site. At fibrous entheses, the tendon or ligament attaches either directly to the bone or indirectly to it via the periosteum. Fibrocartilaginous entheses are sites in which chondrogenesis has occurred and commonly contain four tissue types: dense fibrous connective tissue, uncalcified fibrocartilage, calcified fibrocartilage, and bone. Dysfunction/Responses to Injury Bone Mechanical forces that can affect bone are both internal and external. Internal forces associated with extremes in work or exercise can influence modeling or remodeling (see previous discussion) and occasionally cause fracture (failure of the bone). External forces (trauma) are more commonly associated with damage to the periosteal surface or fracture of the cortex and/or trabecular bone. Hormonal agents, particularly calcitriol and PTH, enter the bone by the bloodstream as described previously. Infectious agents are discussed later in the section on Bone, Inflammation. Defense against mechanical forces includes the structure of the bone and the bone’s ability to model and remodel to adapt to chronic changes in forces applied to it. The dense bone of the cortex enables the bone to resist most external forces. The formation of osteons and cement lines in the cortex (primary remodeling) facilitates dissipation of microcracks and bending of the bone in response to stress. Defense against hormonal agents that are capable of resorbing bone include the protective covering on mineralized surfaces by the lamina limitans and osteoblasts. In addition, hormonal signaling to resorb bone is done through the osteoblast, which has the ability to modulate the resorption signal. Defense against infectious agents is discussed later in the section on Diseases Affecting Multiple Species of Domestic Animals, Bone, Inflammation. The hard tissue of bone can be likened to the rings in a tree that leave clues to the history CHAPTER 16 Bones, Joints, Tendons, and Ligaments 1049 Box 16.2  Bone-Specific Reactions to Injury Disruption of endochondral ossification affects metaphyseal trabeculae and may decrease the rate of bone elongation. Bone changes its shape to adapt to damage and abnormal use. Bone alters its mass in response to systemic disease and altered use. Newly formed bone is woven rather than lamellar. Injured periosteum often responds by forming bone. embedded in its hard structure. Interpreting these clues requires understanding the ways in which bone uniquely responds to injury (Box 16.2). Disruption of endochondral ossification can alter the appearance of the primary spongiosa. Examples of this include growth arrest lines and the growth retardation lattice. Growth arrest lines can be seen in conditions such as debilitating disease or malnutrition, in which multiple nutrient deficiencies are present. The growth plate becomes narrow (growth is impaired), and the metaphyseal face of the plate can be sealed by a layer of bone as a result of transverse trabeculation (trabecular bone forming parallel versus perpendicular to the long axis of the bone), immediately subjacent to the growth plate. If endochondral ossification resumes, this layer of bone becomes separated from the physis and becomes located more distally in the metaphysis. The resulting bony trabeculae that are oriented parallel to the growth plate can be seen grossly and radiographically and are called growth arrest lines (Fig. 16.19, A and B). In cases of acquired impairment of osteoclastic resorption of bone within the primary spongiosa, with continuing elongation from endochondral ossification, a dense band of vertically oriented trabecular bone may be formed subjacent to the growth plate. This is result referred to as a growth retardation lattice (Fig. 16.20). The band is apparent because there is impairment of the normal modeling process that resorbs many primary trabeculae completely and converts the remaining ones into progressively fewer but thicker structures. Diseases that cause growth retardation lattices include canine distemper and bovine viral diarrhea, in which viral infection of osteoclasts results in defects in cell function, resulting in reduced bone resorption. Similarly, toxic damage to osteoclasts, such as in lead poisoning, can cause a growth retardation lattice (“lead line”). Abnormal retention of primary trabeculae also can be seen with congenital defects in the function of osteoclasts (see later discussion of osteopetrosis). The phrase growth retardation lattice is perpetuated here because it is in common use; however, it is important to understand that the lesion is caused by a failure in modeling of the trabeculae rather than by a reduction in longitudinal growth. Weakening or destruction of the matrix of the physeal cartilage, such as occurs in animals with hypervitaminosis A and with manganese deficiency, can lead to premature closure of growth plates. If the entire plate is affected, no further longitudinal growth is possible. If closure is focal, such as can be seen subsequent to localized inflammation or traumatic damage to vessels, the remainder of the growth plate continues to undergo endochondral ossification, resulting in an angular limb deformity. Angular limb deformities (“bent-leg”) involve a deviation from the normal axis of a limb (in the frontal plane) and are defined by the joint involved and the direction that the distal aspect of the limb is deviated. In valgus deformities, the limb distal to the lesion deviates laterally, and in varus deformities, the limb distal to the lesion is deviated medially. Angular limb deformities are thought to be multifactorial in origin. Asymmetric lesions involving an active growth plate are often A B Figure 16.19 Growth Arrest Lines, Long Bone, Metaphysis, Immature Zebra. Gross (A) and microscopic (B) appearance of growth arrest lines. The zebra was ill from a bacterial renal infection and became anorexic. The animal made a brief clinical recovery before euthanasia. The period of inappetence is responsible for the parallel horizontal lines of bone in the metaphysis (growth arrest lines; arrows in both A and B). These lines are the result of transverse (horizontal) orientation of the trabeculae during the period of slowed growth. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) associated with angular limb deformities; however, genetic factors as well as environmental factors such as nutritional disorders, toxins, placentitis, trauma, abnormal bone development, laxity of periarticular soft tissues (supporting structures), and intrauterine or perinatal physical factors may also contribute. For example, foals with congenital hypothyroidism often have angular limb deformities with incomplete (delayed) ossification of the carpal and/or tarsal cuboidal bones and flexural deformities. In dogs, angular limb deformities are most often associated with premature closure of the distal ulnar physis, the conical shape of which results in an increased susceptibility to trauma. Angular limb deformities of young sheep (“bowie”) are often associated with high-energy rations and rapid growth. Osteochondrosis is an important example of a disease caused by disruption of endochondral ossification and is discussed later under disorders of endochondral ossification. The ability of bone to change its shape and size (modeling) to accommodate altered mechanical use, as can occur in hip dysplasia as an example, is called Wolff’s law (Fig. 16.21). Tension and compression are important mechanical factors that affect bone modeling, with formation favored at sites of compression and resorption favored at sites of tension. In addition, trabecular bone aligns along lines of stress. The ways in which bone cells detect altered mechanical use are not precisely known but likely include input from a variety of signals, including stretch receptors on bone cells, streaming potentials, and piezoelectrical activity. Streaming potentials are electrical currents in bone that are detected by the osteocyte-osteoblast 1050 SECTION II Pathology of Organ Systems d d A B Figure 16.20 Growth Retardation Lattice, Bone, Radius, Distal End, Dog. Radiograph (A) and longitudinal section (B) of a growth retardation lattice. The increased bone density (d) of the metaphysis represents failure of osteoclasts to resorb unnecessary primary trabeculae. In this case, the failure of osteoclastic resorption was caused by canine distemper virus infection of osteoclasts. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) * Figure 16.21 Hip Dysplasia, Bone, Femoral Head and Neck, Dog. The femoral head (asterisk) is severely flattened, and periosteal new bone and coalescing osteophytes have formed a massively thickened femoral neck. Macerated specimen. (Courtesy Dr. E.J. Olson, College of Veterinary Medicine, University of Minnesota.) network and are caused by fluid fluxes through canalicular spaces. Piezoelectrical activity refers to the production of electrical currents in bone as a result of deformation of collagen fibers and mineral crystals. Electrical currents can affect cell function (bone formation and resorption) and thus influence bone modeling. Bone mass can be altered to accommodate mechanical use. Normal mechanical use suppresses programmed bone resorptive activity and is required for maintenance of bone mass. Decreased mechanical use reduces this inhibition (allowing resorption to proceed) and suppresses bone formation. The net effect of decreased mechanical use (e.g., casting of a long bone) therefore is a reduced amount of bone as a result of increased resorption and decreased formation (Fig. 16.22). In contrast, increased mechanical use suppresses bone resorption and allows bone mass to increase (Fig. 16.23; E-Fig. 16.13). Chronic suppression of remodeling, however, could result in retention of aged bone and lead to accumulated microcracks, which in turn could override the suppression and stimulate remodeling in these regions. Apoptosis of osteocytes in situations of high bone turnover (both in modeling and remodeling) has recently been identified as a key event in recruitment of osteoclasts. Woven bone is newly formed, hypercellular bone that is deposited in reaction to injury. Although woven bone is normally present in immature individuals, the presence of woven bone in the adult skeleton is considered to be pathologic. The collagen fibers in woven bone are irregularly/randomly arranged rather than being oriented in a lamellar pattern, a change that is best appreciated using polarized light microscopy (Fig. 16.24). In addition, osteocytes are larger and more numerous per unit area than in lamellar bone, and there is no preferred orientation to their lacunae versus in lamellar bone, in which the alignment of the elliptical lacunae is parallel to the lamellae. Over time, woven bone remodels into lamellar bone. The periosteum is programmed to respond to injury by producing woven bone, which usually is oriented perpendicularly to the long axis of the cortex. Although nodular periosteal new bone is sometimes referred to as osteophytes, the use of this term should be restricted to periarticular new bone that occurs in response to joint injury/instability. Reactive periosteal woven bone may be admixed with hyaline cartilage and sometimes is composed predominantly of cartilage. The extent to which cartilage is produced by the periosteum is thought to be a result of the available oxygen. When oxygen tension is low, cartilage proliferation may predominate; however, when oxygen tension is normal, there may be no cartilage present. Cartilage produced in such circumstances can eventually undergo endochondral ossification. In addition, woven bone produced by the periosteum may be remodeled to lamellar bone or may be removed by osteoclastic resorption. In addition to producing woven bone in response to injury, the periosteum also is capable of producing lamellar bone during slower stages of appositional growth of the diaphysis, and this bone also is subject to osteoclastic resorption. During growth, the regions of the cutback zone of the metaphysis, in which CHAPTER 16 Bones, Joints, Tendons, and Ligaments E-Figure 16.13 Osteosclerosis, Bone, Vertebrae, Dog. Osteosclerosis (increased bone per unit of area) is evident in the four vertebrae in the center of the vertebral column. The cancellous bone of the medullary cavities has been obliterated by newly formed compact bone. The osteosclerosis is in response to increased mechanical stress in the bodies of the vertebrae as a result of degeneration and loss of the intervertebral disks between these vertebrae. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) 1050.e1 CHAPTER 16 Bones, Joints, Tendons, and Ligaments A 1051 B Figure 16.22 Bone, Third Phalanx, Rear Legs, Foal. The left leg was in a cast for 2 months to repair an avulsion of gluteal muscles from their insertions. A, Normal right third phalanx. B, Left third phalanx. There is pronounced disuse osteopenia (atrophy) compared with the right third phalanx shown in A. The increase in resorption and decrease in formation associated with disuse has resulted in marked porosity of the cortical and subchondral bone. The cortex now has the appearance of trabecular bone (trabeculation of the cortex). (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) w l Figure 16.23 Osteosclerosis, Intervertebral Disk Disease, Bone, Vertebrae, Horse. Osteosclerosis (increased bone per unit of area) is evident in the two vertebrae (C6-C7, cervical) in the center of the vertebral column image. The cancellous bone of the medullary cavities has been obliterated by newly formed compact bone (arrows). The osteosclerosis is in response to increased mechanical stress in the bodies of the vertebrae as a result of degeneration and loss of the intervertebral disks between these vertebrae. Macerated specimen. (Courtesy Dr. C.S. Carlson, Dr. E.J. Olson, and Dr. M.C. Speltz, College of Veterinary Medicine, University of Minnesota.) the bone diameter is reduced from a larger diameter at the physis to the narrower diameter of the diaphysis, exhibit marked osteoclastic bone resorption at the periosteal bone surface. Infectious inflammation of the periosteum also can lead to marked osteoclastic bone resorption at the periosteal bone surface. The mechanisms of repair of fractures are addressed later in the section on Fracture Repair. Joints Articular Cartilage Although articular cartilage contains metabolically active cells, it has a limited response to injury and minimal capacity for repair that is largely due to its lack of a blood supply. Superficial cartilage defects (cartilage erosions) that do not extend to the level of the subchondral bone persist for long periods with few or no histologic changes. Clusters or clones of chondrocytes (evidence of local chondrocyte replication in response to injury; also referred to as “complex chondron”) may be present, particularly along the margins of the defect, but are ineffective in filling it. Progression of the lesion, with matrix degeneration and eventual loss of the remaining articular cartilage, may occur over time, particularly if thickened (sclerotic) subchondral bone is present subjacent to the defect. In contrast, if a defect involves the full thickness of the articular cartilage (cartilage ulceration) and extends into the subchondral bone, allowing Figure 16.24 Cancellous and Woven Bone, Dog, Hypertrophic Osteopathy, Polarized Microscopy. Preexisting lamellar bone (l) and newly formed periosteal woven bone (w). The woven bone exhibits a disorganized orientation of collagen fibers compared with the adjacent lamellar bone, in which the collagen fibers are arranged in parallel layers. Hematoxylin and eosin (H&E) stain; polarized light micrograph. (Courtesy Dr. C.S. Carlson and Dr. E.J. Olson, College of Veterinary Medicine, University of Minnesota.) mesenchymal cells in the bone marrow access to the defect, it is quickly filled with vascular fibrous tissue that often undergoes metaplasia to fibrocartilage but rarely, if ever, to hyaline cartilage. Formation of fibrocartilage can be hastened in full-thickness cartilaginous defects by exercise or prolonged passive motion. Because articular cartilage is aneural and avascular, injury to articular cartilage is not painful unless the synovium or subchondral bone is involved. Although it does not participate directly in the inflammatory response, articular cartilage is very much affected by inflammation in the synovium, subchondral bone, or subarticular growth (vascularized) cartilage of the epiphysis in young animals. Given that alternating compression and release of normal weight bearing facilitates the diffusion of fluid with nutrients into the articular cartilage and fluid with metabolic waste products out of articular cartilage, it follows that constant compression or lack of weight bearing leads to atrophy (thinning) of articular cartilage. Sterile injury to cartilage can be a consequence of trauma, joint instability, or lubrication failure because of changes in synovial fluid, synovial membrane, or incongruity in joint surfaces. Destruction of 1052 SECTION II Pathology of Organ Systems Normal A Fibrillation Eburnation Subchondral bone B Figure 16.25 Fibrillation. A, Schematic diagram showing the structural changes that characterize fibrillation and loss of articular cartilage as well as eburnation of subchondral bone. In the area of eburnation, the cartilage is missing, and the exposed subchondral bone has increased density. B, Fibrillation and ulceration of articular cartilage, degenerative joint disease, proximal tibia, sagittal section, bull. To the left, the cartilage is frayed (fibrillation), and its surface has the appearance of a shag rug. To the right of the fibrillated region is an ulcer (full-thickness loss of articular cartilage). The cartilage to the right of the ulcer is very thin, indicating erosion (arrow). (B courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) articular cartilage in response to sterile injury and infectious inflammation is mediated by a combination of enzymatic digestion of matrix and failure of matrix production when chondrocytes become degenerate or necrotic. These changes can be initiated by damage to the cartilage directly or may occur indirectly, secondary to lesions in the synovium. Matrix metalloproteinases are enzymes capable of matrix digestion; they are normal constituents of the matrix, but they are present in an inactive form. Matrix metalloproteinases can be broadly categorized as gelatinases, collagenases, and stromelysins. Collagenases are most capable of digestion of collagen fibers; gelatinases digest type I collagen and basement membrane collagens but are less effective against type II collagen of cartilage. Stromelysins destroy noncollagenous proteins. Matrix metalloproteinases can be activated by products of degenerating or reactive chondrocytes and inflammatory cells. In addition, tissue inhibitors of metalloproteinases (TIMPs) are present in the matrix, acting as a control on the destructive effects of activated metalloproteinases. As mentioned previously, proteases capable of degrading aggrecans are called aggrecanases and are members of the ADAM protein family. The loss of proteoglycans from cartilage alters the hydraulic permeability of the cartilage, thereby interfering with joint lubrication and leading to further mechanically induced injury to the cartilage. The loss of proteoglycans, with subsequent inadequate lubrication of the articular surface, leads to disruption of collagen fibers on the surface of articular cartilage. Grossly, the surfaces of affected areas of cartilage are yellow-brown and have a dull, slightly roughened appearance. The yellowing of articular cartilage is in part due to formation of advanced glycation end products (AGEs) that can increase collagen cross-linking, contributing to increased stiffness and increased susceptibility to fatigue failure with age. As more proteoglycans are lost, the collagen fibers condense and fray (fibrillation) with multiple clefts and/or fissures forming along the vertical axis of the arcades of collagen fibers (Figs. 16.25 and 16.26). The vertical axis of the collagen fibers in these arcades is perpendicular to the plane of s Figure 16.26 Degenerative Joint Disease, Hip Dysplasia, Femoral Head, Articular Cartilage, Dog. The superficial cartilage (s) is fibrillated, hypocellular, and contains clusters of chondrocytes (arrows) representing ineffectual attempts at repair. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) movement of the joint. Fibrillation is accompanied by loss of surface cartilage (erosion) and eventual thinning of the articular cartilage. Necrosis of chondrocytes results in hypocellularity of the remaining cartilage. In response to the fibrillation, erosion, and necrosis of chondrocytes, remaining chondrocytes can undergo regenerative hyperplasia (cluster or clone formation), but the ability of chondrocytes in the adult to repair the damaged tissue is ineffective. Loss of articular cartilage can become complete (ulceration), resulting in exposure of subchondral bone, which typically is eburnated (thickened/sclerotic; from the Latin word for “ivory”) and characterized grossly by a polished appearance resulting from direct bone-on-bone contact (Fig. 16.27). Articular Capsule/Synovium/Synovial Fluid Intraarticular prostaglandins, nitric oxide, TNF-α, IL-1, and neurotransmitters—such as substance P, among other cytokines and chemokines—are increased in degenerative and inflammatory joint disease. Prostaglandins and nitric oxide inhibit proteoglycan synthesis in synovium and chondrocytes; this reduction in proteoglycan content can lead to degeneration and loss of the cartilage (see previous discussion). IL-1 and TNF-α are cytokines secreted by activated macrophages (synovial type A cells or subintimal macrophages); they promote secretion of prostaglandins, nitric oxide, and neutral proteases from synovial fibroblasts and chondrocytes. Increasing concentrations of these agents decrease matrix synthesis and increase matrix destruction. Cytokines and growth factors that have anabolic effects on cartilage include IL-6, TGF-β, and insulin-like growth factor (IGF). Lysosomal enzymes (collagenase, cathepsins, elastase, and arylsulfatase) and neutral proteases, which are capable of degrading proteoglycans or collagen, can be derived from inflammatory cells, synovial lining cells, and chondrocytes. The synovial membrane commonly responds to injury by villous hypertrophy and hyperplasia (Fig. 16.28), hypertrophy and hyperplasia of synoviocytes, and pannus formation (see later discussion). Villous hypertrophy/hyperplasia occurs with or without synovitis. The proportions of type A (macrophages) and type B (fibroblastlike) cells in the synovium also can change in various disease processes. Fragments of articular cartilage can adhere to the synovium, where they are surrounded by macrophages and giant cells. Larger pieces of detached cartilage (as in osteochondrosis dissecans) can float free and survive as chondral or osteochondral fragments (sometimes referred to as “joint mice”) that continue to remain viable through nutrients supplied from synovial fluid. CHAPTER 16 Bones, Joints, Tendons, and Ligaments 1053 h A s Figure 16.29 Pannus, Rheumatoid-Like Arthritis, Proximal Radius and Ulna, Dog. Fibrovascular granulation tissue (pannus) covers all articular surfaces. Also see Figs. 16.30 and 16.31. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) B Figure 16.27 Degenerative Joint Disease. A, Humeral head with eburnation, tiger. Extensive loss of articular cartilage with thickening (sclerosis) of subchondral bone (eburnation) such that the humeral head (h) in the af­fected area has become smooth and shiny. B, Hip dysplasia, femoral head with eburnation, dog. The femoral head viewed in a sagittal plane. The head is flattened and ulcerated. The ulcerated region appears darker (arrow) because of congestion of blood vessels in the marrow spaces of the subchondral bone (s). The zone of attachment of the round ligament to the head of the femur has been destroyed. (A courtesy Dr. A. Wuenschmann, College of Veterinary Medicine, University of Minnesota. B courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) f Figure 16.28 Synovial Villous Hyperplasia, Hip Dysplasia, Coxofemoral Joint, Articular Capsule, and Femoral Head, Dog. There is marked villous synovial hyperplasia (arrows). The femoral head (f) has extensive loss of articular cartilage with thickening of subchondral bone that has become smooth and shiny. The extent of the proliferation is unusually severe for hip dysplasia. Microscopically, villous synovial hyperplasia is routinely accompanied by variable lymphoplasmacytic inflammation that is independent of the cause of the articular damage. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) Inflammatory cell infiltrates (see the discussion on infectious and noninfectious arthritis in the section on Inflammatory Lesions) in the synovial membrane can impair fluid drainage from the joint and can cause joint fluid to lose some of its lubricating properties as the result of degradation of hyaluronic acid by the superoxide-generating systems of neutrophils. Pannus can develop in association with chronic infectious fibrinous synovitis and with some immune-mediated diseases; the classic example is rheumatoid arthritis. Pannus is a fibrovascular and histiocytic tissue (also called an inflammatory granulation tissue) that arises from the synovial membrane and spreads as a membrane over articular cartilage (Figs. 16.29 and 16.30). In the pannus, tissue histiocytes and monocytes of bone marrow origin transform into macrophages and they, along with the collagenases from fibroblasts, cause lysis and destruction of the underlying cartilage (Fig. 16.31). In time, if both opposing cartilaginous surfaces are involved, the fibrous tissue can unite the surfaces, causing fibrous ankylosis (fusion of the joint). In some cases of immune-mediated arthritis, pannus is present in the subchondral bone marrow (bone marrow pannus), as well as in the synovium, and may penetrate into the overlying articular cartilage. Sterile degenerative changes in articular cartilage are often accompanied by the formation of periarticular osteophytes (Fig. 16.32; E-Fig. 16.14) and by some degree of secondary synovial hyperplasia and/or inflammation. The synovitis is characterized by the presence of variable numbers of plasma cells, lymphocytes, and macrophages in the synovial subintima (beneath the layers of synoviocytes) and by hyperplasia and hypertrophy of synovial lining cells. The pathogenesis of this synovitis is not known but is suspected to result, at least partially, from the presence of degenerate cartilage debris within the joint. The pathogenesis of osteophytes (newly formed nodular outgrowths of fibrocartilage and bone, formed at the interface between cartilage and the periosteum) also is unclear. They can arise from mesenchymal cells with chondro-osseous potential within the synovial membrane at the junction of the synovial membrane with the perichondrium/periosteum, just peripheral to the articular cartilage, or on the surface of the bone where the articular CHAPTER 16 Bones, Joints, Tendons, and Ligaments E-Figure 16.14 Osteophytes, Degenerative Joint Disease, Distal Femur, Dog. Note the large number of osteophytes (arrows) along the lateral and medial margins of the trochlear ridges. (Courtesy Dr. H. Leipold, College of Veterinary Medicine, Kansas State University; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia.) 1053.e1 1054 SECTION II Pathology of Organ Systems * * s Figure 16.30 Pannus, Rheumatoid-Like Arthritis (Experimentally Induced), Distal Articular Cartilage, Tibia, Rat. The experimentally induced rheumatoid-like arthritis was produced by injecting Freund’s adjuvant and Mycobacterium butyricum into the subcutis at the base of the tail. The pathogenesis of “adjuvant arthritis” is uncertain, other than it appears to be T lymphocyte mediated. Macrophages and other chronic (mononuclear) inflammatory cells may also be present in some forms of pannus (not shown here). Here, fibrovascular repair tissue (pannus) is seen arising from the synovium (left) and growing onto the surface of the articular cartilage (arrows), which is relatively undamaged at this stage of the disease. Hematoxylin and eosin (H&E) stain. Asterisk, Articular cartilage. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) Figure 16.31 Pannus, Rheumatoid-Like Arthritis (Experimentally Induced), Articular Cartilage, Distal Tibia, Rat. Pannus originating from the synovium (left) is invading and destroying the articular cartilage (arrows) and subchondral bone (s). Macrophages and other chronic (mononuclear) inflammatory cells are present in the pannus (box with dashed lines). Hematoxylin and eosin (H&E) stain. Asterisk, Articular cartilage. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) capsule and the periosteum merge. Osteophytes do not grow continuously, but once formed, they persist as multiple periarticular spurs of bone. These spurs can be confined within the joint cavity if they arise from the perichondrium or can be protrusions from the periosteal surface of the bone if they arise from the insertion site of the joint capsule with the periosteum. Osteophytes can result from mechanical instability within the joint, causing stretching or tearing of the insertions of the articular capsule or ligaments, or they can form from stimulation by cytokines such as TGF-β that are released from reactive or degenerating mesenchymal cells within the joint. Because of their antiinflammatory effects, glucocorticoids often are therapeutically injected into joints. Although the usual result is decreased pain and inflammation, glucocorticoid injection sometimes is followed by a rapid progression of degenerative changes within the joint that is designated “steroid arthropathy.” These degenerative changes relate to the antianabolic effects of glucocorticoids on chondrocytes, in which synthesis of cartilaginous matrix is reduced, proteoglycans are depleted, repair is retarded, and the mechanical strength of cartilage is reduced. Subchondral Bone With the loss of matrix proteoglycans in degenerate articular cartilage, the subchondral bone bears an increased amount of concussive force. The bone responds to the increased mechanical use by decreasing resorption and increasing formation, resulting in a net increase in amount of bone per unit area (increased subchondral bone density or subchondral sclerosis). If the cartilage ulcerates to the level of the bone and the joint is still being used, the surface of the dense subchondral bone can become smooth and shiny (eburnation) (see Fig. 16.27, A). There is interest in the possible role subchondral bone may play in initiating cartilage damage in degenerative joint disease (DJD), as some studies have reported an increase in subchondral bone thickness/density before the development of articular cartilage lesions. Some believe that this dense bone is less effective in dissipating normal concussive forces and causes some of the impact to be deflected back into the articular cartilage, causing injury to the chondrocytes. Figure 16.32 Osteophytes, Degenerative Joint Disease, Distal Femur, Dog. Note the large number of osteophytes (arrows) along the lateral and medial margins of the trochlear ridges. Macerated specimen. (Courtesy Dr. E.J. Olson, College of Veterinary Medicine, University of Minnesota.) Tendons and Ligaments The site where ligament or tendon attaches to bone is known as an enthesis but is also called an insertion site or an osteotendinous or osteoligamentous junction. Entheses are vulnerable to acute or overuse injuries in sports as the result of stress concentration at the hardsoft tissue interface. Abnormal bony proliferations located in these regions are termed enthesophytes. The initial stage of repair of tendons and ligaments involves formation of scar tissue to provide continuity at the injury site. For tendons CHAPTER 16 Bones, Joints, Tendons, and Ligaments in particular, mobility must be maintained during healing to prevent or at least decrease the formation of adhesions and increase strength. The sequence of repair includes three phases: (1) acute inflammatory response, (2) cell and matrix proliferation, and (3) remodeling and maturation. The acute response phase usually involves the formation of a hematoma, which activates the release of chemotactic factors, including TGF-β, IGF-1, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). Inflammatory cells are attracted from the surrounding tissues to engulf and resorb the clot, cellular debris, and foreign material. Fibroblasts are recruited to the site to begin to synthesize components of the extracellular matrix, and angiogenic factors that are released during this phase initiate the formation of a vascular network. During the cell proliferation phase, recruitment and proliferation of fibroblasts continue because these cells are responsible for the synthesis of collagens, proteoglycans, and other extracellular matrix components, which initially are arranged randomly. At this point in the repair process, the extracellular matrix is composed largely of type III collagen. At the end of the proliferative stage, the repair tissue is highly cellular and contains relatively large amounts of water and an abundance of extracellular matrix components. The remodeling stage begins 6 to 8 weeks after injury and is characterized by a decrease in cellularity, reduced matrix synthesis, a decrease in type III collagen, and an increase in type I collagen synthesis. The type I collagen fibers are organized longitudinally along the tendon axis and are responsible for the mechanical strength of the regenerating tissue. Despite multiple ongoing phases of remodeling, the repair tissue never achieves the characteristics of normal tendon. Aging Bone Aging Aging changes of bone have been well characterized in human beings and include both quantitative and qualitative changes (alterations in the dynamics of bone cell populations, changes in bone architecture, accumulation of microfractures, localized disparity in the concentration of deposited minerals, changes in crystalline properties of mineral deposits, and changes in the protein content of matrix material). The net result of these changes is a loss of bone architecture, density, and strength. In most animals studied and in human beings, bone gets stiffer, and the cross-sectional area is reduced with age, leading to increased stress and increased bone deformation. Tendons and Ligaments Aging Aging changes in tendons and ligaments that have been documented in human beings include poorly characterized vascular and compositional changes that alter their mechanotransduction, biology, healing capacity, and biomechanical function. Summary Aging changes in bone, tendons, and ligaments of domestic animals are presumed to be similar to those reported in human beings but are much less well documented in part because of the fact that most domestic animals are reproductively active throughout the majority of their life span and do not experience the dramatic reduction in sex hormones that occurs, for example, in postmenopausal women. Age is an important risk factor in many of the degenerative orthopedic diseases in domestic animals, including but not limited to osteoarthritis, intervertebral disk disease, tendon/ligament rupture, and spondylosis. Portals of Entry/Pathways of Spread Bone Infectious agents can enter bone directly through the periosteum and cortex or through the vasculature. Agents can gain access * * p 1055 * Figure 16.33 Embolic (Suppurative) Osteomyelitis and Physitis, Bone, Distal Radius, Foal. The pale region in the metaphysis (asterisks) extending upward to the top middle border of the illustration represents suppurative inflammation and necrosis. It is bordered by a red rim of active hyperemia. A fissure (the linear space along the metaphyseal margin of the physis [p]) and the porosity (darker regions within the growth plate, right) are the result of bone lysis (primary trabeculae) and destruction of cartilage canal blood vessels in the growth plate, respectively, caused by the infection. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) through the periosteum by means of trauma that may or may not break the bone or by extension from adjacent inflammation, as in periodontal tissue (e.g., periodontitis progressing to mandibular or maxillary osteomyelitis) or the middle ear (otitis media extending into the bone, resulting in osteomyelitis of the tympanic bulla). Blood vessels gain access to the marrow cavity of the diaphysis and metaphysis through the nutrient foramen. The primary blood supply of the epiphysis in young animals is the epiphyseal artery, multiple branches of which arborize into the growth plate, providing vascularization of the proliferative zone (see Figs. 16.9 and 16.11). Bloodborne bacterial infection of bone in the perinatal animal may originate from the umbilicus (e.g., omphalitis/ omphalophlebitis/omphaloarteritis) or, more commonly, by the oral-pharyngeal route. In theory, hematogenous osteomyelitis can begin in any capillary bed in bone in which viable bacteria localize. In practice, it occurs most commonly in young animals and is localized typically at the zone of vascular invasion on the metaphyseal side of the growth plate (Figs. 16.33 and 16.34, A) or immediately subjacent to the AECC (Fig. 16.34, B; E-Fig. 16.15), where capillaries in both sites make sharp bends to join medullary veins (Fig. 16.35). In these locations, bacterial localization is apparently facilitated by slow flow and turbulence of blood, a lower phagocytic capacity, and a discontinuous endothelial lining. In addition, no vascular anastomoses are located in this region; therefore, thrombosis of these capillaries results in bone infarction that is a predisposing factor for bacterial localization. From this nidus, the inflammation can extend into other structures, including the overlying joint cavity for AECC lesions (see Fig. 16.34, B) and the epiphysis, periosteum, or joint cavity for physeal lesions (Fig. 16.36; also see Fig. 16.35). Joints Microbial and other agents enter the joints via hematogenous spread (Fig. 16.37). For example, neonatal bacteremia secondary to omphalitis or oral-intestinal entry commonly leads to polyarthritis. Bacteria can also reach the joint by direct inoculation, as in a puncture wound, by extension from adjacent periarticular soft tissues, or by extension from adjacent bone. CHAPTER 16 Bones, Joints, Tendons, and Ligaments 1055.e1 * * A B E-Figure 16.15 Embolic (Suppurative) Osteomyelitis, Bone, Distal Femur, Medial Trochlear Ridge, Transverse Section, Horse. A, Oblique view of articular cartilage and transverse section showing embolic osteomyelitis (asterisk). B, The suppurative osteomyelitis (asterisk) has extended from its site of origin in the cancellous bone into the articular-epiphyseal complex, with resulting collapse and fragmentation of the articular cartilage. (Courtesy Dr. S.E. Weisbrode, College of Veterinary Medicine, The Ohio State University.) 1056 SECTION II Pathology of Organ Systems and resorption, resulting in varying degrees of reactive bone formation and bone lysis. The exudate associated with some acute infections in the medullary cavity can increase the pressure in this region and cause compression of the nutrient artery, resulting in ischemic necrosis. If resorbed cortical bone is replaced by fibrous repair tissue, the bone can become unstable. For more detailed information on inflammation, infectious agents, and immune defense mechanisms, see Chapter 3, Inflammation and Healing; Chapter 4, Mechanisms of Microbial Infections; and Chapter 5, Diseases of Immunity, respectively. Joints * The cellular and humoral defenses against infectious agents are no different in the joint from those in other tissues. However, because articular cartilage has such limited ability to regenerate, progression to DJD could occur after inflammation that either destroys the ability of synovium to provide nutrients and synovial fluid to the cartilage or destroys areas of the cartilage. For more detailed information on inflammation, infectious agents, and immune defense mechanisms, see Chapter 3, Inflammation and Healing; Chapter 4, Mechanisms of Microbial Infections; and Chapter 5, Diseases of Immunity, respectively. p A Tendons/Ligaments n The cellular and humoral defenses against infectious agents are no different in tendons and ligaments from those in other tissues. For more detailed information on inflammation, infectious agents, and immune defense mechanisms, see Chapter 3, Inflammation and Healing; Chapter 4, Mechanisms of Microbial Infections; and Chapter 5, Diseases of Immunity, respectively. Diseases Affecting Multiple Species of Domestic Animalsf Bone B Figure 16.34 Embolic (Suppurative) Osteomyelitis, Bone, Horse. A, Distal tibial physis. Localized area of infection and bone lysis (asterisk) within physis and proximal metaphysis. p, Physis. B, Talus. Suppurative osteomyelitis has extended from its site of origin in the cancellous bone into the articular-epiphyseal cartilage complex (AECC) via cartilage canal vessels (arrows). The affected bone contains multiple cavities, is separated by a cleft (arrowhead) from the overlying cartilage, and is pale and opaque (necrosis [n]). (Courtesy Dr. A. Wuenschmann, College of Veterinary Medicine, University of Minnesota.) Tendons/Ligaments Infection of tendons and ligaments usually requires a sharp force injury or puncture wound because of the dense connective tissue covering of the tendon (epitenon) or ligament (epiligament). Less commonly, there may be extension of infection from infected skin or from an adjacent joint. The sequelae of bacterial infection of tendons and ligaments most often include adhesions and accompanying loss of function. Defense Mechanisms/Barrier Systems Bone The defense against infectious agents is no different in bone than in other tissues. However, the consequences of an inflammatory response can greatly affect the structure and function of bone. Many soluble inflammatory mediators can increase both bone formation Abnormalities of Growth and Development There are many potential, suspected, or known genetic disorders (see E-Table 1.2) of bone. Improved technology and extensive research in the field has led to advancements in our knowledge of the genes underlying musculoskeletal diseases. Given the rapidity of progress in the field of genetics, detailing every known genetic variant associated with diseases of the musculoskeletal system in veterinary species is beyond the scope of this text. Many diseases may also vary in causative genetic mutation or mode of inheritance between species or even between breeds within a species. For example, cranial cruciate ligament (CCL) disease, a common skeletal disease in the dog, seems to be a polygenic (complex) trait, with occurrence related to several genetic and environmental factors. In one study, three single nucleotide polymorphisms (SNPs) were significantly associated with the risk of CCL disease in Newfoundland dogs, while 13 significant SNPs were identified to best predict risk for CCL disease in Labrador retrievers. A different study found over 100 SNPs within 99 risk loci associated with CCL disease in Labrador retrievers. If necropsy findings are consistent with a possible genetic disorder, samples of a cell-rich tissue (liver, spleen) may be collected unfixed with sterile technique and frozen to preserve genomic DNA until identification of an appropriate laboratory for further assessment. The process of genome assessment can be lengthy (months to fExamples of known or suspected genetic disorders are listed in E-Table 1.2.