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) i nhibitors, 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 ro le of p38 MAPK, we have studied its activation in osteoblasts and chondrocy tes, following treatment with a panel of proinflammatory and osteotropic ag ents. In osteoblasts, significant activation of p38 MAPK was observed follo wing 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 chond rocytes and an SV40-immortalized human chondrocyte cell line, T/C28A4. SE 2 03580, a selective inhibitor of p38 MAPK, inhibited IL-l and TNF-induced p3 8 MAPK activity and IL-6 production (IC(50)s 0.3-0.5 muM) in osteoblasts an d 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 b one resorption in vitro in a dose-dependent manner (IC(50)s 0.3-1 muM) Thes e data support the contention that p38 MAPK plays a central role in regulat ing 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 indicat es that selective inhibition of the p38 MAPK pathway may have therapeutic u tility in joint diseases such as rheumatoid arthritis (RA]. J. Cell. Physio l. 187: 294-303, 2001. (C) 2001 Wiley-Liss, Inc.