The Breakdown and Repair of Articular Cartilage

The structure of the extracellular matrix plays a critical role in the function of articular cartilage. In normal joints, this matrix is constantly being degraded and repaired by chondrocytes. Since matrix synthesis and matrix degradation occur at equal rates, the two processes are normally kept in balance. Both the repair and breakdown processes are controlled by extracellular growth factors and cytokines. A disturbance or alteration in these chemical messengers can initiate disease.

In normal articular cartilage, the turnover rate of extracellular matrix components is slow and the capacity for repair is limited. Collagen turnover is particularly slow. Proteoglycans are more susceptible to enzymatic breakdown and are continually being resynthesized, however.

Insulin-like growth factor-I (TGF-I) and transforming growth factor-b (TGF-b) are synthesized by chondrocytes and stored in the extracellular matrix. When activated, they stimulate chondrocytes to synthesize proteoglycans. IGI-I and TGF-b regulate matrix metabolism in normal cartilage and may play a role in matrix repair in patients with osteoarthritis.

The chondrocytes also synthesize a number of enzymes that can degrade the matrix structure. These are released into the extracellular matrix in an inactive form. Among the enzymes that have been identified as playing a major role in the degradation of collagen and aggrecan molecules are metalloproteinases, such as collagenase, stromelysin, and gelatinase; and serine proteases, such as tissue plasminogen activator.

The activation of these degradative enzymes is held in check by inhibitors, such as tissue inhibitor of metalloproteinase (TIMP) and plasminogen activator inhibitor (PA1-I). TIMP  and PA1-I are synthesized by chondrocytes and limit the degradative activity of active metalloproteinases and plasrainogen activator. If TIMP and PA1-I are destroyed or present insufficient quantities, metalloproteinases and plasmin are free to act on matrix components. Normally, there is a balance between these inhibitors and the degradative enzymes they inhibit.

Thee cytokine interleukin-1 (IL-1) plays an importane role in the stimulation of cartilage degradation. Il-1, which is produced by chondrocytes and other cells in the joint, stimulates the synthesis of degradative enzymes and inhibits the production of proteoglycan. IL-1 may also inhibit the synthesis of TIMP.

Other cytokines that appear to act synergistically with IL-1 to promote matrix breakdown are tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6). All of these cytokines are routinely found in inflamed joints.