Disease Modifying Drugs

The development of disease-modifying drugs (DMDs) for OA is still in its early stage. Cytokines, such as IL-1^ and TNF-a, are therapeutic targets [36,51], and their inhibition would theoretically reduce the inflammatory component of OA. Inhibitors of MMPs have shown promise in animal models [11, 65], but clinical trials in humans have been disappointing [57]. An alternative approach is osteoarthritis gene therapy, where gene transfer to the synovium would enhance synthesis of the cartilaginous matrix or inhibit its breakdown. Therapeutic effects of IL-1Ra (receptor antagonist) gene transfer have been confirmed in three different experimental models of OA [25].

Perhaps the greatest potential for therapeutic intervention lies in preventing chon-drocytes from expressing degradative enzymes. This might involve inhibition of expression or, ideally, preventing the phenotypic change to degradative chondrocytes. Neutraceuticals, such as fish oil, glucosamine, and chondroitin sulfate, are widely used supplements that seem to slow disease progression (reviewed in [17, 34]). Although evidence is still limited, their beneficial effects seem to be due to inhibiting the expression of degradative enzymes in articular chondrocytes. Omega-3 fatty acids (present in fish oil) have been shown to inhibit IL-1^-induced expression of several degradative enzymes, as well as inhibiting mediators of inflammation in human articular chondrocytes [18]. Chondroitin sulfate inhibits MMP-3 synthesis by chondrocytes [58]. Therapy would be considerably advanced if we understood what causes normal articular chondrocytes to change to degradative chondrocytes. Because this change is transmitted to daughter cells, the changes may be epigenetic, a possibility worth exploring.

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