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Bone Morphogenetic Protein 2 Stimulates Osteoclast Differentiation and Survival Supported by Receptor Activator of Nuclear Factor-B Ligand

Department of Biochemistry, Showa University School of Dentistry (K.I., N.U., T.K., T.S., N.T.), Tokyo 142-8555; Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology (S.I., N.U.), Okazaki 444-8585; Center for Experimental Medicine, Institute of Medical Science, University of Tokyo (H.Y.), Tokyo 108-8639; Snow Brand Milk Products Co., Ltd. (K.H.), Tochigi 329-0512, Japan; and St. Vincent’s Institute of Medical Research (J.M.W.Q., M.T.G., T.J.M.), Fitzroy, Victoria 3065, Australia

Address all correspondence and requests for reprints to: Dr. Naoyuki Takahashi, Department of Biochemistry, Showa University School of Dentistry, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail: nao{at}dent.showa-u.ac.jp

Bone is a major storage site for TGFß superfamily members, including TGFß and bone morphogenetic proteins. It is believed that these cytokines are released from bone during bone resorption. Recent studies have shown that both RANKL and macrophage colony-stimulating factor are two essential factors produced by osteoblasts for inducing osteoclast differentiation. In the present study we examined the effects of bone morphogenetic protein-2 on osteoclast differentiation and survival supported by RANKL and/or macrophage colony-stimulating factor. Mouse bone marrow-derived macrophages differentiated into osteoclasts in the presence of RANKL and macrophage colony-stimulating factor. TGFß superfamily members such as bone morphogenetic protein-2, TGFß, and activin A markedly enhanced osteoclast differentiation induced by RANKL and macrophage colony-stimulating factor, although each cytokine alone failed to induce osteoclast differentiation in the absence of RANKL. Addition of a soluble form of bone morphogenetic protein receptor type IA to the culture markedly inhibited not only osteoclast formation induced by RANKL and bone morphogenetic protein-2, but also the basal osteoclast formation supported by RANKL alone. Either RANKL or macrophage colony-stimulating factor stimulated the survival of purified osteoclasts. Bone morphogenetic protein-2 enhanced the survival of purified osteoclasts supported by RANKL, but not by macrophage colony-stimulating factor. Both bone marrow macrophages and mature osteoclasts expressed bone morphogenetic protein-2 and bone morphogenetic protein receptor type IA mRNAs. An EMSA revealed that RANKL activated nuclear factor-B in purified osteoclasts. Bone morphogenetic protein-2 alone did not activate nuclear factor-B, but rather inhibited the activation of nuclear factor-B induced by RANKL in purified osteoclasts. These findings suggest that bone morphogenetic protein-mediated signals cross-communicate with RANKL-mediated ones in inducing osteoclast differentiation and survival. The enhancement of RANKL-induced survival of osteoclasts by bone morphogenetic protein-2 appears unrelated to nuclear factor-B activation.

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