Putting Some Muscle into Osteoarthritis

Osteoarthritis, the most common joint disease, results from the complex interplay of biochemical, metabolic, and biomechanical factors and is characterized, in part, by the progressive loss of articular cartilage. Aggrecan and collagen, the major molecular constituents of articular cartilage, confer stiffness on compression and tensile strength, respectively. Evidence that the metabolic turnover rates of these molecules are increased in osteoarthritic cartilage has led investigators to search for enzymes responsible for their degradation in the hope that pharmacologic inhibitors might be developed to prevent the development or slow the progression of osteoarthritis.

In vitro, several matrix metalloproteinases (MMPs) degrade the core protein of aggrecan through the cleavage of the interglobular domain between Asn³⁴¹ and Phe³⁴². However, the predominant fragment of the core protein found in the synovial fluid of patients with osteoarthritis and in the medium of chondrocyte cultures after stimulation with interleukin-1 is generated by cleavage between Glu³⁷³ and Ala³⁷⁴, suggesting that in vivo proteolysis at the more distal site is important in the breakdown of cartilage in osteoarthritis. Efforts to produce primary Glu³⁷³ -Ala³⁷⁴ cleavage with a large number of proteases have been unsuccessful; this suggests that an unidentified enzyme, “aggrecanase,” is responsible for this cleavage [1]. Recent evidence [2] suggests that aggrecanase may be a novel MMP.

The predominant collagen in articular cartilage, type II collagen, is responsible for the structural integrity of the tissue. Chondrocytes can produce three collagenases that are capable of cleaving the triple helical region of this collagen: MMP-1 (collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3). The last of these represents a major product of cartilage stimulated with interleukin-1, and it hydrolyzes type II collagen much more efficiently than do the other collagenases in cartilage [3]. Whether pharmacologic inhibition of collagenase or …