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J. Biol. Chem., Vol. 278, Issue 23, 21258-21266, June 6, 2003

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Impaired Osteoclast Formation in Bone Marrow Cultures of Fgf2 Null Mice in Response to Parathyroid Hormone^*

Yosuke Okada , Aldemar Montero , Xuxia Zhang , Takanori Sobue , Joseph Lorenzo , Thomas Doetschman , J. Douglas Coffin ¶ and Marja M. Hurley  ||

From the Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-1850, Department of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 45267-0524, and ^¶Department of Pharmaceutical Sciences, School of Pharmacy and Allied Health Sciences, University of Montana, Missoula, Montana 59812

Fibroblast growth factor (FGF)-2 and parathyroid hormone (PTH) are potent inducers of osteoclast (OCL) formation, and PTH increases FGF-2 mRNA and protein expression in osteoblasts. To elucidate the role of endogenous FGF-2 in PTH responses, we examined PTH-induced OCL formation in bone marrow cultures from wild type and mice with a disruption of the Fgf2 gene. FGF-2-induced OCL formation was similar in marrow culture from both genotypes. In contrast, PTH-stimulated OCL formation in bone marrow cultures or co-cultures of osteoblast-spleen cells from Fgf2-/mice was significantly impaired. PTH increased RANKL mRNA expression in osteoblasts cultures from both genotypes. After 6 days of treatment, osteoprotegerin protein in cell supernatants was 40-fold higher in vehicle-treated and 30-fold higher in PTH-treated co-cultures of osteoblast and spleen cells from Fgf2-/mice compared with Fgf2+/+ mice. However, a neutralizing antibody to osteoprotegerin did not rescue reduced OCL formation in response to PTH. Injection of PTH caused hypercalcemia in Fgf2+/+ but not Fgf2-/mice. We conclude that PTH stimulates OCL formation and bone resorption in mice in part by endogenous FGF-2 synthesis by osteoblasts. Because RANKL- and interleukin-11-induced OCL formation was also reduced in bone marrow cultures from Fgf2-/mice, we further conclude that endogenous FGF-2 is necessary for maximal OCL formation by multiple bone resorbing factors.

Received for publication, February 28, 2003

^* This work was supported in part by National Institutes of Health Grant AR-46025 (to M. M. H.). 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.

^|| To whom correspondence should be addressed: Division of Endocrinology and Metabolism, The University of Connecticut Health Center, Farmington, CT 06030-1850. Tel.: 203-679-2129; Fax: 203-679-1258; E-mail: hurley{at}exchange.uchc.edu.

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