Outline of Veterinary Skeletal Pathology

contents Ch 3, p 3 Chapter 4, Page 1 Ch 5, p 1 

Outline of Veterinary Skeletal Pathology

Chapter 4 - Joints, Basic Principles

A. Structure and composition.
1. Microanatomy. Cartilage is a type of connective tissue composed exclusively of cells called chondrocytes and a highly specialized extracellular matrix.
a. Types of cartilage.
(1) hyaline cartilage forms the model for fetal bones and makes up the physes, apophyses, and articular surfaces of developing bones. It gets its name because it has a glassy, homogeneous, amorphous matrix. Lacunae are spaces located throughout the cartilage in which cartilage cells lie.
(a) chondrocytes in tissue sections, are distorted, because during preparation, there is loss of glycogen and lipid from the cells. They are highly metabolically active cells and are responsible for the manufacture of the cartilage matrix.
(b) cartilage matrix is composed of collagen fibrils that are arranged in a three dimensional felt-like pattern. The ground substance is composed of glycosaminoglycans: hyaluronic acid, chondroitin sulfate, and keratan sulfate. These substances are joined together in a macromolecular structure (proteoglycan monomer) that has a form like a test-tube brush. Within the tissue, numerous proteoglycan monomers are attached by link protein to hyaluronic acid to form large aggregates that associate with the collagen fibrils. Ground substance is hydrophilic, and joint cartilage contains 60-78% water. The glycosaminoglycans are not uniformly distributed in the cartilage. High concentrations immediately surround lacunae. Intermediate concentrations of sulfated proteoglycans surrounding cell groups form the territorial matrix (fig. IIa-1) Lesser concentrations are seen in the interterritorial matrix.
(2) fibrocartilage is found in menisci, intervertebral disks and attachment sites of ligaments and tendons to bone (enthesis). This type of cartilage is similar to hyaline cartilage, except it contains bundles of thick collagenous fibers that are obvious by light microscopy. The presence of fibrocartilage usually indicates that resistance to compressive or shear forces is required. This is the type of tissue that replaces hyaline cartilage (e.g. articular cartilage) during the process of repair.

2. Macroanatomy.
a. Synovium, synovial fluid, and joint capsule. The joint capsule consists of two layers, an outer fibrous layer, fibrous capsule, and an inner layer called the synovial membrane. The synovial membrane is a thin, vascular lining that covers the inner surfaces of the joint capsule and intra-articular ligaments and tendons. It is composed of a subsynovial connective tissue layer and a discontinuous lining of synoviocytes that are phagocytic or fibroblastic cells. The synovial membrane is pink, usually smooth, and glistening. Synovial villi project into the joint at specialized regions, such as niches between the large fat folds, and they are particularly prominent in certain places such as a joint out-pouching or cul-de-sac. They are larger and more regularly spaced in animals than man, and they are more prominent in large domestic animals such as the horse. Synovial fluid is formed as a plasma dialysate from capillaries, and substances, such as hyaluronic acid, is secreted by synoviocytes. Synovial fluid is normally clear and viscid and is colorless to yellow (carotenoids in those species that have them in their plasma e.g. horse, dog, beef cattle). The gross appearance of synovial fluid, the synovial membrane, and articular cartilage can be altered by local congestion and autolysis. Hemolysis of blood causes synovial fluid and articular cartilage to be stained red.
b. Articular cartilage. Grossly, normal articular cartilage appears white and glistening, but it is milky and opaque in areas where it is thicker. In thin areas that overlie bone marrow, the cartilage may be translucent and slightly blue (fig. IIa-2). On cut section, the thickness of the articular cartilage varies not only from joint to joint within an individual but also from region to region within a given joint. There is a wide range of thickness in articular cartilage between animal species.
c. Synovial fossae (figs. IIa-3, IIa-4) are normal anatomical structures that appear as non-articular depressions in the joint surface. They are absent at birth, and the time of appearance, size, shape, and persistence of any given fossa varies. It is important to recognize synovial fossae as normal anatomical structures and to distinguish them from areas of articular collapse or lesions of osteochondrosis or osteoarthritis.
d. Meniscus, ligaments and tendons. The color and transparency of menisci and articular discs vary from region to region and reflect their thickness and composition. Thin portions of menisci and discs are translucent and have a blue-gray color. With increasing thickness, opacity increases and color changes gradually from blue to white. Most ligaments grossly appear white and have a fibrous texture, although ligaments that contain significant amounts of elastic tissue, such as the ligamentum nuchae, have a yellow color.

B. Normal Development of Joints
1. Joint types. Most of the movable articulations are synovial joints (diarthroses), but some such as intervertebral discs have only limited motion (amphiarthroses).

2. Formation.
a. Synovial joints are formed early in the process of limb bud differentiation and are vulnerable to the effect of teratogens during this period. During the growth period, the circumference of the articular surface increases as the bone increases in length and width. Beneath the articular cartilage is its growth zone (fig. Ia-13) called the articular-epiphyseal complex cartilage (AE complex) that disappears as the animal matures.
b. Intervertebral disks. The axial skeleton also undergoes segmentation in early development, and defects in development of the vertebral bodies may be due to an early defect in the recombination of sclerotomic masses that form the vertebral body and intervertebral disk. The intervertebral disk appears first as the perichondral disk, a band of densely cellular tissue surrounding the notochord. The annulus fibrosus develops by self-differentiating from the peripheral part of the perichondral disk. The nucleus pulposus is first represented by an aggregate of notochord cells in the intervertebral region, and in lumbar disks it grows very rapidly during late fetal life.

C. Reaction of Joints to Injury
1. Tissue responses.
a. Synovial membrane.
(1) Primary response. The synovial lining cells react to injurious agents by hypertrophy and hyperplasia (fig. IIa-5), thus increasing their synthetic and phagocytic functions. Cells increase in number, become plump, and contain abundant rough endoplasmic reticulum. Inflammatory reactions that cause synovial cells to increase phagocytic activity also increase synthesis of hydrolase enzymes and production of lysosomes. The synovial membrane has a tremendous capacity to undergo villus proliferation as a feature of low-grade inflammation. With stimulation of the synovial membrane by inflammation, synovial vessels may proliferate, producing a fibrovascular membrane or pannus that may spread across the articular surface and may penetrate defective articular cartilage (fig. IIa-6).
(2) Secondary responses within the synovium include deposition of hemosiderin, fibrosis of articular capsule that thickens it, and mineralization within the subsynovial connective tissue or joint capsule. In rare instances of chronic inflammation, there may be metaplasia in the subsynovial connective tissue to form osteochondral nodules.
b. Articular cartilage.
(1) Necrosis. Too much pressure causes cells in the superficial cartilage zone to become necrotic (fig. IIa-7), and there is loss of matrix. Also, cartilage necrosis may result from alterations in the synovial fluid, for example purulent exudate or blood filling the joint cavity.
(2) Chondromalacia and fibrillation. Too little load results in decreased synthesis of proteoglycans, and chondromalacia (soft cartilage) results. This is followed by cartilage fibrillation (figs. IIa-8, IIa-9) where the normal collagen fibrils within the cartilage matrix become more apparent (probably due to loss of proteoglycan). Histologically, cracks and crevices develop causing fragmentation of the remaining cartilage and formation of longitudinal clefts.
(3) Joint mice are fragments of cartilage that break off from the joint surface (fig. IIa-10). They fall into the joint cavity and may survive, grow, and ossify as they continue to receive nourishment from the synovial fluid that bathes them.
(4) Cell multiplication. Whenever there is cartilage cell necrosis or loss of the superficial cartilage layers, remaining cartilage cells may divide producing cell clones called chondrones (fig. IIa-11). The ability of articular cartilage to replace itself following injury is limited and somewhat dependent on the age of the animal. In adult animals, the response of articular cartilage to trauma also is dependent largely on the depth of the injury. Superficial lacerations that do not penetrate subchondral bone are not repaired, as the insult evokes only a short-lived metabolic and enzymatic response that fails to provide sufficient cells or matrix to heal the smallest injury.
c. Subchondral bone.
(1) Granulation tissue response. If the injury penetrates through articular cartilage into subchondral bone, typically, granulation tissue is laid down (fig. IIa-12). The edges of the cartilage wound are united with fibrous tissue, and the subchondral bone marrow space becomes filled with granulation tissue. Later, at the base of the articular cartilage lesion in the region of granulation tissue that is in contact with the injured osseous trabeculae, formation of bone is brisk and extends towards the articular cartilage. However, the formation of reactive bone is only sufficient to fill the defect in the bone.
(2) Fibrocartilage response. As indicated above, injury or gaps in cartilage that extend into subchondral bone induce a granulation tissue response. In addition to formation of reactive bone, there sometimes is formation of substantial amounts of fibrocartilage that may incompletely fill the cartilage defect (fig. IIa-10).
(3) Subchondral pseudocysts. Following deep cartilage injury that penetrates bone, granulation tissue is formed in the subchondral bone. The reactive mesenchymal tissue sometimes undergoes myxomatous degeneration rather than forming fibrocartilage. This is thought to occur when pressure is exerted on the tissue caused by the synovial fluid that penetrates subchondral bone as occurs in chronic stages of degenerative arthritis or osteochondrosis. Subchondral bone in the myxomatous region is selectively resorbed to form a cavity filled with myxomatous tissue, and surrounding trabeculae become thick and produce a zone of sclerosis to form a pseudocyst (figs. Ic-10, Ic-11).

2. Mechanism of joint injury.
a. Infectious agents. The underlying biochemical mechanisms involved in immune-mediated and nonimmune articular diseases are similar, in that the production of local factors can lead to chondromalacia or degradation of articular cartilage. Infectious agents spread hematogenously and may localize either within synovial fluid or periarticular tissues. Bacteria emerge from blood vessels in the loose stroma of the synovial membrane of the articular capsule and enter the synovial fluid. The infectious agent determines, in part, the characteristics of the inflammatory response that follows.
b. Nonimmune-mediated processes. The inflammatory response induced by viable organisms may degrade articular cartilage by several mechanisms:
(1) Acute reaction. Small molecular weight peptidoglycans derived from killed bacteria induce acute polyarthritis by a nonimmune-mediated process. This initial inflammatory response is probably mediated by mast cell degranulation.
(2) Lysosomes. Lysosomal enzymes (collagenase, cathepsines, elastase, and arylsulfatase) released from polymorphonuclear leukocytes and from synovial, bone, and cartilage cells degrade proteoglycan.
(3) Proteases. Metalloproteases (collagenases, gelatinases and stromelysin) are members of a single gene family and are capable of degrading every component of the extracellular matrix. These enzymes are responsible for much of the tissue destruction observed in inflammatory joint disease. The inflammatory cytokines, interleukin-1 and tumor necrosis factor-alpha, are among the most potent inducers of metalloproteinase expression. Neutral proteases, which degrade collagen and proteoglycans, are produced by synovial cells and chondrocytes.
(4) Superoxide radicals. Synovial cells can be induced to generate hydrogen peroxide constitutively by an inflammatory response. Enzymatically generated superoxide or peroxide depolymerizes polysaccharides and degrades synovial fluid and cartilage.
c. Immune-mediated processes. Heat-killed bacteria can induce arthritis, and this is intimately associated with the bacterial cell-wall peptidoglycans. The development of immune-mediated arthritis is dependent on antigens being deposited in the joint and development of delayed hypersensitivity. Antigens have been found within phagocytic cells, synovial fluid and the synovial membrane. The role of sequestered antigen in maintenance of the chronic inflammation is dependent on long-lasting leakage of antigen from phagocytes.
(1) Cells. Monocytes/macrophages, T and B lymphocytes, synoviocytes, and capillary endothelial cells are involved in the process. Synoviocytes are believed to be an important source of metalloproteases, cytokines as well as other inflammatory mediators, all of which contribute to the destruction of cartilage and eventually the entire joint.
(2) Effector molecules:
(a) lymphotoxin. A nonimmunoglobin, T-cell derived molecule acts similarly to tumor necrosis factor (see below).
(b) immune complexes. Immune complexes are trapped in the joint collagenous tissue found in articular cartilage, menisci, and synovial membranes and provoke an inflammatory response. These immune complexes can be phagocytosed by macrophages or synoviocytes, which then produce interleukin-1. Alternatively, the activation of complement by immune complexes produces C3a and C5a, which are known to induce interleukin-1 secretion.
(c) prostaglandin. Prostaglandins are compounds derived from arachidonic acid via the cyclooxygenase pathway. They are synthesized by most cells including endothelial and inflammatory cells. Prostaglandins play an important role in inflammation by potentiating the effects of histamine and bradykinin. Prostaglandin E2 acts as a vasodilator, produces pain, and causes fever by acting on the hypothalamus. It inhibits cartilage proteoglycan production and stimulates formation of reactive bone.
(d) interleukin-1 (IL-1). IL-1 is produced by many cell types, particularly monocytes and macrophages, and is a general mediator of inflammation. IL-1 can stimulate synoviocytes and chondrocytes in articular cartilage to release neutral proteases and prostaglandin E2. It is a potent inducer of metalloproteinases and causes cartilage and bone catabolism. Local inflammation is not necessary for Il-1-cartilage interaction as it is produced by synoviocytes under some conditions, such as slight trauma.
(e) Tumor Necrosis Factor-alpha (TNF-α). TNF-α is a major mediator of inflammation. It is produced by mononuclear cells and acts as a paracrine molecule to regulate the production of IL-1. It is an inducer of metalloproteinases. In arthritis, TNF-α is produced in the synovial membrane, at the synovium-pannus junction, and by endothelium.
d. Biomechanical injury. Degradative changes in articular cartilage, which lead to erosion of cartilage down to subchondral bone is a feature of both inflammatory and degenerative joint disease. Since interleukin-1 is produced by phagocytic synoviocytes, local inflammation does not seem to be necessary for its secretion. IL-1 inhibition of the secretion of collagen and proteoglycan is probably important in the pathogenesis of degenerative joint disease.

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