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p38 Mitogen-Activated Protein Kinase Is Crucially Involved in Osteoclast Differentiation But Not in Cytokine Production, Phagocytosis, or Dendritic Cell Differentiation of Bone Marrow Macrophages

Institute for Oral Science (X.L., Y.K., N.T.), Department of Biochemistry (N.U., N.S.), Matsumoto Dental University, Nagano 399-0781, Japan; Department of Biochemistry (M.T.), School of Dentistry, Showa University, Tokyo 142-8555, Japan; and Department of Periodontology (N.S.), School of Dentistry, Aichi Gakuin University, Aichi 464-8651, Japan

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

We previously reported that p38 MAPK signaling is required for osteoclast differentiation but not osteoclast function. Here we further investigated the role of p38 MAPK in the function and differentiation of mouse bone marrow macrophages (BMM), common precursors of osteoclasts and dendritic cells. Lipopolysaccharide (LPS) activated the p38 MAPK signaling pathway in BMM by sequential phosphorylation of MAPK kinase 3/6, p38 MAPK, and activating transcription factor-2. Treatment of BMM with SB203580, a p38 MAPK inhibitor, suppressed LPS-induced phosphorylation of activating transcription factor-2. LPS stimulated production of IL-1ß, TNF, and IL-6 in BMM, and SB203580 failed to inhibit the LPS-induced cytokine production. BMM incorporated latex beads via phagocytosis, and SB203580 had no effect on this phagocytosis. BMM differentiated into dendritic cells when treated with granulocyte macrophage colony-stimulating factor together with CD40 ligand, TNF, or LPS, and SB203580 failed to inhibit this differentiation. Thus, p38 MAPK-mediated signals are not involved in either BMM function or BMM differentiation into dendritic cells. The differentiation of BMM into osteoclasts in response to receptor activator of nuclear factor-B ligand or TNF was strongly inhibited by SB203580. These findings emphasize the crucial roles of p38 MAPK-mediated signaling in osteoclast differentiation.

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