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This version published online on July 24, 2003
Endocrinology, doi:10.1210/en.2003-0166
A more recent version of this article appeared on November 1, 2003
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Submitted on February 3, 2003
Accepted on July 18, 2003

p38 MAPK is Crucially Involved in Osteoclast Differentiation But Not in Cytokine Production, Phagocytosis Or Dendritic Cell Differentiation of Bone Marrow Macrophages

Xiaotong Li1, Nobuyuki Udagawa1, Masamichi Takami1, Nobuaki Sato1, Yasuhiro Kobayashi1, and Naoyuki Takahashi1*

1 Institute for Oral Science (X.L., Y.K., N.T.), Department of Biochemistry (N.U.), Matsumoto Dental University, Nagano, Japan; Department of Biochemistry (M.T.), School of Dentistry, Showa University, Tokyo, Japan; Department of Periodontology (N.S.), School of Dentistry, Aichi Gakuin University, Nagoya, Japan

* To whom correspondence should be addressed. E-mail: takahashinao{at}po.mdu.ac.jp.

We reported that p38 mitogen-activated protein kinase (MAPK) signaling is required for osteoclast differentiation but not osteoclast function (Endocrinology 143:3105-3113, 2002). Here we further investigated the role of p38 MAPK in the function and differentiation of mouse bone marrow macrophages (BMM{phi}), common precursors of osteoclasts and dendritic cells. Lipopolysaccharide (LPS) activated the p38 MAPK signaling pathway in BMM{phi} by sequential phosphorylation of MAPK kinase 3/6, p38 MAPK, and activating transcription factor-2 (ATF2). Treatment of BMM{phi} with SB203580, a p38 MAPK inhibitor, suppressed LPS-induced phosphorylation of ATF2. LPS stimulated production of interleukin 1{beta}, tumor necrosis factor-{alpha} (TNF{alpha}), and interleukin 6 in BMM{phi}, and SB203580 failed to inhibit the LPS-induced cytokine production. BMM{phi} incorporated latex beads via phagocytosis, and SB203580 had no effect on this phagocytosis. BMM{phi} differentiated into dendritic cells when treated with granulocyte macrophage colony-stimulating factor together with CD40 ligand, TNF{alpha} or LPS, and SB203580 failed to inhibit this differentiation. Thus, p38 MAPK-mediated signals are not involved in either BMM{phi} function or BMM{phi} differentiation into dendritic cells. The differentiation of BMM{phi} into osteoclasts in response to receptor activator of nuclear factor-{kappa}B ligand or TNF{alpha} was strongly inhibited by SB203580. These findings emphasize the crucial roles of p38 MAPK-mediated signaling in osteoclast differentiation.
Key words: Osteoclast • p38 MAPK • Lipopolysaccharide • Cytokine production • Phagocytosis • Dendritic cell




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