Our understanding of the pathogenesis of osteoarthritis has evolved considerably over the past decade. We now know that osteoarthritis is a dynamic disease process characterized by a disruption in the normal balance between degradation and repair in articular cartilage and subchondral bone. This leads to an abrasion of the articular cartilage on weight-bearing surfaces and the formation of new bone at the edges of the joint. Ultimately, the result is a deterioration of joint funtion.
Many investigators believe that osteoarthritis is initiated by mechanical stress to the joint that alters chondrocyte metabolism. This results in an increased production of degradative enzymes. Cytokines, such as IL-1 and TNF-a, and a variety of growth factors. An imbalance is created between the production of degradative enzymes and the TIMPs that inhibit them. This eventually leads to degradation of the extracellular matrix.
In addition to this degradative process, an ongoing repair process likes place in osteoarthritis characterized by increased synthesis of collagen and proteoglycan. The collagen produced is abnormal, however, and an immature form of aggrecan is synthesized.
It is interesting to note that the structure of aggrecan molecules in the extracellular matrix changes with aging. These chantes include a decrease in the length of chondroitin sulfate chains and an increase in the number and length of keratan sulfate chains. These changes many reflect alterations inthe synthesis of collagen and aggrecan or the cumulative effects of degradative enzymes on the matrix structure.
Similar changes in the composition of aggrecan have been noted in patients with osteoarthritis. Although new proteoglycan continues to be synthesized, even in advanced osteoarthritis, the form of aggrecan produced in an immature, fetal form. This suggests that the chondrocytes revert back to an immature pattern of synthesis.
Summary Points
Many investigators believe that osteoarthritis is initiated by mechanical stress to the joint that alters chondrocyte metabolism. This results in an increased production of degradative enzymes. Cytokines, such as IL-1 and TNF-a, and a variety of growth factors. An imbalance is created between the production of degradative enzymes and the TIMPs that inhibit them. This eventually leads to degradation of the extracellular matrix.
In addition to this degradative process, an ongoing repair process likes place in osteoarthritis characterized by increased synthesis of collagen and proteoglycan. The collagen produced is abnormal, however, and an immature form of aggrecan is synthesized.
It is interesting to note that the structure of aggrecan molecules in the extracellular matrix changes with aging. These chantes include a decrease in the length of chondroitin sulfate chains and an increase in the number and length of keratan sulfate chains. These changes many reflect alterations inthe synthesis of collagen and aggrecan or the cumulative effects of degradative enzymes on the matrix structure.
Similar changes in the composition of aggrecan have been noted in patients with osteoarthritis. Although new proteoglycan continues to be synthesized, even in advanced osteoarthritis, the form of aggrecan produced in an immature, fetal form. This suggests that the chondrocytes revert back to an immature pattern of synthesis.
Summary Points
- Osteoarthritis is characterized by degenerative changes in articular cartilage and by an ongoing repair process.
- Chondrocytes are articular cartilage cells which produce and maintain the extracellular matrix. They occupy only about 1% to 2% of the articular cartilage volume.
- The three primary constituents of the extracellular matrix are water, proteoglycans and collagen.
- Chondrocytes synthesize metalloproteinases and other proteases that can degrade the matrix proteins. These are held in check by inhibitors, such as TIMP and PAI-1.
- Interleukin-1 (IL-1) plays an important role in the stimulation of cartilage degradation. Tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) appear to act synergistically with IL-1 to promote matrix breakdown.
- Insulin-like growth factor-1 (IGF-1) and transforming growth factor-b (TGF-b) are synthesized by chondrocytes and stimulate chondrocytes to synthesize proteoglycans. They play an important role in the matrix repair process.
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