Cytokine modulation of chondrocyte metabolism--in vivo and in vitro effects of piroxicam.

Changes in the macromolecular proteolycan (PG) and collagen of the cartilage matrix may culminate in irreparable tissue destruction. Molecular modifications appear to result from: (A) exogenous proteinases, (B) endogenous chondrocyte proteinases whose synthesis and release is modulated by exogenous non-enzymatic cytokines (CKs) and (C) quantitative and/or qualitative alterations in chondrocyte PG and collagen synthesis which are potentially induced by exogenous CKs. Studies have recently been initiated to determine the effect of piroxicam on the synthesis and activity of such metabolic regulatory CKs in patients with rheumatoid arthritis and osteoarthritis, and in age-, sex-, and race-matched controls. Therapeutic doses of piroxicam alone had no effect on the anabolic or catabolic function of chondrocytes. Current studies concern the effect of piroxicam on: (a) spontaneous and lectin-driven production by peripheral blood monocytes and T-cells of trypsin-sensitive, heat-labile CKs (interleukin 1, lymphokine) which, in a protein- and RNA-synthesis-dependent manner, induce a concentration and duration of substrate exposure dependent release of chondrocyte PG- and collagen- degrading neutral proteinases in cartilage organ and chondrocyte suspension culture systems; (b) spontaneous and lectin-driven synthesis by peripheral blood T-cells of lymphokines capable of suppressing chondrocyte PG, glycosaminoglycan, protein, collagen and nucleic acid synthesis in a quantitatively reversible manner; (c) pathological synovial membrane synthesis of such catabolic-inducing and anabolic-modulatory CKs. These experimental model system are reviewed together with preliminary data on the effect of piroxicam.