Joint Protective Mechanisms and Their Failure

Joint protectors include: joint capsule and ligaments, muscle, sensory afferents, and underlying bone. Joint capsule and ligaments serve as joint protectors by providing a limit to excursion, thereby fixing the range of joint motion.

Synovial fluid reduces friction between articulating cartilage surfaces, thereby serving as a major protector against friction-induced cartilage wear. This lubrication function depends on the molecule lubricin, a mucinous glycoprotein secreted by synovial fibroblasts whose concentration diminishes after joint injury and in the face of synovial inflammation.

The ligaments, along with overlying skin and tendons, contain mechanoreceptor sensory afferent nerves. These mechanoreceptors fire at different frequencies throughout a joint's range of motion, providing feedback by way of the spinal cord to muscles and tendons. As a consequence, these muscles and tendons can assume the right tension at appropriate points in joint excursion to act as optimal joint protectors, anticipating joint loading.

Muscles and tendons that bridge the joint are key joint protectors. Their co-contractions at the appropriate time in joint movement provide the appropriate power and acceleration for the limb to accomplish its tasks. Focal stress across the joint is minimized by muscle contraction that decelerates the joint before impact and assures that when joint impact arrives, it is distributed broadly across the joint surface.

The bone underneath the cartilage may also provide a shock-absorbing function, as it may give way subtly to an oncoming impulse load.

Failure of these joint protectors increases the risk of joint injury and OA. For example, in animals, OA develops rapidly when a sensory nerve to the joint is sectioned and joint injury induced. Similarly, in humans, Charcot arthropathy, which is a severe and rapidly progressive OA, develops when minor joint injury occurs in the presence of posterior column peripheral neuropathy. Another example of joint protector failure is rupture of ligaments, a well-known cause of the early development of OA.

Cartilage and Its Role in Joint Failure

In addition to being a primary target tissue for disease, cartilage also functions as a joint protector. A thin rim of tissue at the ends of two opposing bones, cartilage is lubricated by synovial fluid to provides an almost frictionless surface across which these two bones move. The compressible stiffness of cartilage compared to bone provides the joint with impact-absorbing capacity. Both the smooth frictionless surface and the compressive stiffness of cartilage serve as protective mechanisms preventing joint injury.

Since the earliest changes of OA may occur in cartilage and abnormalities there can accelerate disease development, understanding the structure and physiology of cartilage is critical to an appreciation of disease pathogenesis. The two major macromolecules in cartilage are type 2 collagen, which provides cartilage its tensile strength, and aggrecan, a proteoglycan macromolecule linked with hyaluronic acid, which consists of highly negatively charged glycosaminoglycans. In normal cartilage, type 2 collagen is woven tightly, constraining the aggrecan molecules in the interstices between collagen strands, forcing these highly negatively charged molecules into close proximity with one another. The aggrecan molecule, through electrostatic repulsion of its negative charges, gives cartilage its compressive stiffness. Chondrocytes, the cells within this avascular tissue, synthesize all elements of the matrix. In addition, they produce enzymes that break down the matrix and cytokines and growth factors, which in turn provide autocrine/paracrine feedback that modulates synthesis of matrix molecules (Fig. 326-3). Cartilage matrix synthesis and catabolism are in a dynamic equilibrium influenced by the cytokine and growth factor environment and by mechanical stress. While chondrocytes synthesize numerous enzymes, especially matrix metalloproteinases (MMP), there are only a few that are critical in regulating cartilage breakdown. Type 2 cartilage is degraded primarily by MMP-13 (collagenase 3), with other collagenases playing a minor role. Aggrecan degradation is complex but appears to be a consequence, in part, of activation of aggrecanase 1 (ADAMTS-4) and perhaps of MMPs. Both collagenase and aggrecanase act primarily in the territorial matrix surrounding chondrocytes; however, as the osteoarthritic process develops, their activities and effects spread throughout the matrix, especially in the superficial layers of cartilage.

The chondrocyte and its products, type II collagen, aggrecan and enzymes which degrade these structures along with molecules stimulating chondrocytes. [From AR Poole et al: Ann Rheum Dis 61 (S): ii78, 2002.]

The synovium and chondrocytes synthesize numerous growth factors and cytokines. Chief among them is interleukin (IL) 1, which exerts transcriptional effects on chondrocytes, stimulating production of proteinases and suppressing cartilage matrix synthesis. In animal models of OA, IL-1 blockade prevents cartilage loss. Tumor necrosis factor (TNF) may play a similar role to that of IL-1. These cytokines also induce chondrocytes to synthesize prostaglandin E2, nitric oxide, and bone morphogenic protein 2 (BMP-2), which together have complex effects on matrix synthesis and degradation. Nitric oxide inhibits aggrecan synthesis and enhances proteinase activity, whereas BMP-2 is a potent stimulator of anabolic activity. At early stages in the matrix response to injury and in the healthy response to loading, the net effect of cytokine stimulation may be matrix turnover but, ultimately, excess IL-1 triggers a process of matrix degradation. Enzymes in the matrix are held in check by activation inhibitors, including tissue inhibitor of metalloproteinase (TIMP). Growth factors are also part of this complex network, with insulin-like growth factor type 1 and transforming growth factor playing prominent roles in stimulating anabolism by chondrocytes.

While healthy cartilage is metabolically sluggish, with slow matrix turnover and a net balance of synthesis and degradation, cartilage in early OA or after an injury is highly metabolically active. In the latter situation, stimulated chondrocytes synthesize enzymes and new matrix molecules, with those enzymes becoming activated in the matrix, causing release of degraded aggrecan and type 2 collagen into cartilage and into the synovial fluid. OA cartilage is characterized by gradual depletion of aggrecan, an unfurling of the tightly woven collagen matrix, and loss of type 2 collagen. With these changes comes increasing vulnerability of cartilage, which no longer has compressive stiffness.