Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther

Mitogen-activated protein kinase (MAPK) pathways are impli-cated in joint destruction in rheumatoid arthritis (RA) by mod-ulating the production and functions of inflammatory cytokines. Although p38 MAPK (p38) participates in signaling cascades leading to osteolysis in arthritis, the mechanisms of its action in this process remain incompletely understood. Here, we found that the osteoclast (Ocl) precursors expressed p38, but not p38, p38, and p38 isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-B ligand (RANKL) resulted in p38 activation. Importantly, Ocl development in-duced by RANKL or RANKL and tumor necrosis factor (TNF)- was blocked with the novel p38 inhibitor 4-(3-(4-chlorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (SC-409). To validate in vitro data, p38 role was further investigated in streptococcal cell wall (SCW)-induced arthritis in rats. We found that SCW-induced joint swelling and bone destruction were attenuated by SC-409. Mechanistically, the data show that SCW-stimulated DNA binding activity of the transcription factor myocyte-enhancing factor 2 C, which is downstream o