IL-1-and TNF-induced bone resorption is mediated by p38 mitogen activated protein kinase

We have previously shown that p38 mitogen-activated protein kinase IMAPK) inhibitors, which block the production and action of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), are effective in models of bone and cartilage degradation. To further investigate the role of p38 MAPK, we have studied its activation in osteoblasts and chondrocytes, following treatment with a panel of proinflammatory and osteotropic agents. In osteoblasts, significant activation of p38 MAPK was observed following treatment with IL-l and TNF, but not parathyroid hormone, transforming growth factor-p (TCF-beta), 1,25(OH)(2)D-3, insulin-like growth factor-1 (IGF-1), or IGF-II. Similar results were obtained using primary bovine chondrocytes and an SV40-immortalized human chondrocyte cell line, T/C28A4. SE 203580, a selective inhibitor of p38 MAPK, inhibited IL-l and TNF-induced p38 MAPK activity and IL-6 production (IC(50)s 0.3-0.5 muM) in osteoblasts and chondrocytes. In addition, IL-l and TNF also activated p38 MAPK in fetal rat long bones and p38 MAPK inhibitors inhibited IL-1- and TNF-stimulated bone resorption in vitro in a dose-dependent manner (IC(50)s 0.3-1 muM) These data support the contention that p38 MAPK plays a central role in regulating the production of, and responsiveness to, proinflammatory cytokines in bone and cartilage. Furthermore, the strong correlation between inhibition of kinase activity and IL-1 and TNF-stimulated biological responses indicates that selective inhibition of the p38 MAPK pathway may have therapeutic utility in joint diseases such as rheumatoid arthritis (RA]. J. Cell. Physiol. 187: 294-303, 2001. (C) 2001 Wiley-Liss, Inc.