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p38 MAPK-Mediated Signals Are Required for Inducing Osteoclast Differentiation But Not for Osteoclast Function

Institute for Oral Science (X.L., N.T.), the Department of Biochemistry (N.U.), Matsumoto Dental University, Nagano 399-0781, Japan; the Department of Biochemistry (K.I., K.S.), School of Dentistry, Showa University, Tokyo 142-8555, Japan; the Department of Periodontology (Y.M.), Aichi Gakuin University, Nagoya 464-8651, Japan; the Department of Oral Microbiology (T.N.), Kyushu Dental College, Fukuoka 803-8580, Japan; and the Research Center for Genomic Medicine (T.S.), Saitama Medical School, Saitama 350-1241, Japan

Address all correspondence and requests for reprints to: Naoyuki Takahashi, Ph.D., Institute for Dental Science, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano 399-0781, Japan. E-mail: . takahashinao{at}po.mdu.ac.jp

Receptor activator of nuclear factor-B ligand (RANKL)-induced signals play critical roles in osteoclast differentiation and function. SB203580, an inhibitor of p38 MAPK, blocked osteoclast formation induced by 1,25-dihydroxyvitamin D₃ and prostaglandin E₂ in cocultures of mouse osteoblasts and bone marrow cells. Nevertheless, SB203580 showed no inhibitory effect on RANKL expression in osteoblasts treated with 1,25-dihydroxyvitamin D₃ and prostaglandin E₂. RANKL-induced osteoclastogenesis in bone marrow cultures was inhibited by SB203580, suggesting a direct effect of SB203580 on osteoclast precursors, but not on osteoblasts, in osteoclast differentiation. However, SB203580 inhibited neither the survival nor dentine-resorption activity of osteoclasts induced by RANKL. Lipopolysaccharide (LPS), IL-1, and TNF all stimulated the survival of osteoclasts, which was not inhibited by SB203580. Phosphorylation of p38 MAPK was induced by RANKL, IL-1, TNF, and LPS in osteoclast precursors but not in osteoclasts. LPS stimulated phosphorylation of MAPK kinase 3/6 and ATF2, upstream and downstream signals of p38 MAPK, respectively, in osteoclast precursors but not in osteoclasts. Nevertheless, LPS induced degradation of IB and phosphorylation of ERK in osteoclasts as well as in osteoclast precursors. These results suggest that osteoclast function is induced through a mechanism independent of p38 MAPK-mediated signaling.

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