GENERATION OF NITRIC-OXIDE BY LAPINE MENISCAL CELLS AND ITS EFFECT ONMATRIX METABOLISM - STIMULATION OF COLLAGEN PRODUCTION BY ARGININE

Slices of lapine meniscus produced large amounts of nitric oxide after stimulation with interleukin-l, tumor necrosis factor alpha, or a mix ture of lapine synovial cytokines known as chondrocyte-activating fact ors. Monolayer cultures of meniscal cells produced from the proteolysi s of meniscal tissue contained a mixed population of chondrocytic and fibroblastic cells. These cultures also produced large amounts of nitr ic oxide in response to cytokines. Monolayer cultures of meniscal cell s produced by the explant method, in contrast, were uniformly fibrobla stic and did not produce nitric oxide in response to cytokines. We con clude that menisci contain two populations of cells, one fibroblastic and the other chondrocytic. The chondrocytic cells are responsible for generating most of the nitric oxide in response to cytokines. Endogen ously generated nitric oxide suppressed the synthesis of collagen and proteoglycan by menisci but protected proteoglycan from the catabolic effects of interleukin-1. The inhibitory effect of nitric oxide on col lagen synthesis occurred without greatly altering the abundance of mRN As encoding the various collagen alpha chains. During further investig ation, arginine was unexpectedly found to stimulate the synthesis of c ollagen and, to a lesser degree, of noncollagenous proteins but not of proteoglycans. Fragments of meniscus, but not meniscal cells in monol ayer culture, increased their production of matrix metalloproteinases, lactate, and, especially, prostaglandin E-2 in response to interleuki n-1. Inhibition of nitric oxide production with N-G-monomethyl-L-argin ine enhanced production of matrix metalloproteinases but had little ef fect on the synthesis of lactate or prostaglandin E-2.