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J. Biol. Chem., Vol. 278, Issue 26, 23971-23977, June 27, 2003

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Induction of Osteoclast Differentiation by Runx2 through Receptor Activator of Nuclear Factor-B Ligand (RANKL) and Osteoprotegerin Regulation and Partial Rescue of Osteoclastogenesis in Runx2^–/– Mice by RANKL Transgene^*

From the ^aDepartment of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, ^bDepartment of Orthodontics and Dentofacial Orthopedics, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, ^cDepartment of Orthopaedic Surgery Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, ^dDepartment of Pharmacology, Faculty of Pharmaceutical Science, Setsunan University, Hirakata, Osaka 573-0101, ^gInstitute for Biomedical Research, Teijin Ltd., Hino, Tokyo 191-8512, ^eResearch Institute of Life Science, Snow Brand Milk Products, Co., Ltd., Shimotsuga-gun, Tochigi 329-0512, and ^kJapan Science and Technology Corporation, Kawaguchi City, Saitama Prefecture 332-0012, Japan

Receptor activator of nuclear factor-B ligand (RANKL), osteoprotegerin (OPG), and macrophage-colony stimulating factor play essential roles in the regulation of osteoclastogenesis. Runx2-deficient (Runx2^–/–) mice showed a complete lack of bone formation because of maturational arrest of osteoblasts and disturbed chondrocyte maturation. Further, osteoclasts were absent in these mice, in which OPG and macrophage-colony stimulating factor were normally expressed, but RANKL expression was severely diminished. We investigated the function of Runx2 in osteoclast differentiation. A Runx2^–/– calvaria-derived cell line (CA120–4), which expressed OPG strongly but RANKL barely, severely suppressed osteoclast differentiation from normal bone marrow cells in co-cultures. Adenoviral introduction of Runx2 into CA120–4 cells induced RANKL expression, suppressed OPG expression, and restored osteoclast differentiation from normal bone marrow cells, whereas the addition of OPG abolished the osteoclast differentiation induced by Runx2. Addition of soluble RANKL (sRANKL) also restored osteoclast differentiation in co-cultures. Forced expression of sRANKL in Runx2^–/– livers increased the number and size of osteoclast-like cells around calcified cartilage, although vascular invasion into the cartilage was superficial because of incomplete osteoclast differentiation. These findings indicate that Runx2 promotes osteoclast differentiation by inducing RANKL and inhibiting OPG. As the introduction of sRANKL was insufficient for osteoclast differentiation in Runx2^–/– mice, however, our findings also suggest that additional factor(s) or matrix protein(s), which are induced in terminally differentiated chondrocytes or osteoblasts by Runx2, are required for osteoclastogenesis in early skeletal development.

Received for publication, March 10, 2003 , and in revised form, April 14, 2003.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^f Present address: Dept. of Pharmacology, Jichi Medical School, Kawachi-gun, Tochigi 329-0498, Japan.

^h Present address: Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, Tokyo 140-8710, Japan.

ⁱ Present address: Center for Experimental Medicine, Inst. of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

^j Present address: Research Center for Genomic Medicine, Saitama Medical School, Hidaka, Saitama 350-1241, Japan.

^l To whom correspondence should be addressed: Dept. of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-7590; Fax: 81-6-6879-7796; E-mail: komorit{at}imed3.med.osaka-u.ac.jp.

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