CYTOKINE-INDUCED INHIBITION OF BONE-MATRIX PROTEINS IS NOT MEDIATED BY PROSTAGLANDINS

Interleukin-1 (IL-1) and tumor necrosis factor (TNF), two pleiotropic cytokines produced in inflammatory processes, inhibit bone matrix bios ynthesis and stimulate prostanoid formation in osteoblasts. In the pre sent study, the importance of prostaglandin formation in IL-1 and TNF- induced inhibition of osteocalcin and type I collagen formation has be en examined. In the human osteoblastic cell line MG-63, IL-1 alpha (10 -1000 pg/ml), IL-1 beta (3-300 pg/ml) and TNF-alpha (1-30 ng/ml) stimu lated prostaglandin E(2) (PGE(2)) formation and inhibited 1,25(0H)(2)- vitamin D3-induced osteocalcin biosynthesis as well as basal productio n of type I collagen. Addition of PGE(2) or increasing the endogenous formation of PGE(2) by treating the cells with arachidonic acid, brady kinin, Lys-bradykinin or des-Arg(9)-bradykinin, did not affect osteoca lcin and type I collagen formation in unstimulated or 1,25(OH)(2)-vita min D3-stimulated osteoblasts. Four non-steroidal antiinflammatory dru gs, indomethacin, flurbiprofen, naproxen and meclofenamic acid, inhibi ted basal, IL-1 beta-and TNF-alpha-stimulated PGE(2) formation in the MG-63 cells without affecting IL-1 beta- or TNF-alpha-induced inhibiti on of osteocalcin and type I collagen formation. In isolated, non-tran sformed, human osteoblast-like cells, IL-1 beta and TNF-beta stimulate d PGE(2) formation and concomitantly inhibited 1,25(OH)(2)-vitamin D3- stimulated osteocalcin biosynthesis, without affecting type I collagen formation. In these cells, indomethacin and flurbiprofen abolished th e effects of IL-1 beta and TNF-alpha on prostaglandin formation withou t affecting the inhibitory effects of the cytokines on osteocalcin bio synthesis. These data show that IL-1 and TNF inhibit osteocalcin and t ype I collagen formation in osteoblasts independently of prostaglandin biosynthesis and that non-steroidal antiinflammatory drugs do not aff ect the effects of IL-1 and TNF on bone matrix biosynthesis.