Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL)

The receptor activator of NF-kappa B ligand (RANKL) induces osteoclast diff erentiation from bone marrow cells in the presence of macrophage colony-sti mulating factor, We found that treatment of bone marrow cells with SB203580 inhibited osteoclast differentiation via inhibition of the RANKL-mediated signaling pathway. To elucidate the role of p38 mitogen-activated protein ( MAP) kinase pathway in osteoclastogenesis, we employed RAW264 cells which c ould differentiate into osteoclastlike cells following treatment with RANKL . In a dose-dependent manner, SB203580 but not PD98059, inhibited RANKL-ind uced differentiation. Among three MAP kinase families tested, this inhibiti on profile coincided only with the activation of p38 MAP kinase. Expression in RAW264 cells of the dominant negative form of either p38 alpha MAP kina se or MAP kinase kinase (MKK) 6 significantly inhibited RAM(L-induced diffe rentiation of the cells, These results indicate that activation of the p38 MAP kinase pathway plays an important role in RANKL-induced osteoclast diff erentiation of precursor bone marrow cells.