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Semaphorin 3B Is a 1,25-Dihydroxyvitamin D₃-Induced Gene in Osteoblasts that Promotes Osteoclastogenesis and Induces Osteopenia in Mice

Department of Pharmacology (A.L.M.S., X.Z., D.R.D., P.N.M.), Case Western Reserve University, Cleveland Ohio 44106; and Women’s Heath Research Institute (Y.P.K., B.S.K.), Wyeth Research, Collegeville, Pennsylvania 19426

Address all correspondence and requests for reprints to: Paul N. MacDonald, Ph.D., Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106. E-mail: paul.macdonald{at}case.edu.

The vitamin D endocrine system is important for skeletal homeostasis. 1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃] impacts bone indirectly by promoting intestinal absorption of calcium and phosphate and directly by acting on osteoblasts and osteoclasts. Despite the direct actions of 1,25(OH)₂D₃ in bone, relatively little is known of the mechanisms or target genes that are regulated by 1,25(OH)₂D₃ in skeletal cells. Here, we identify semaphorin 3B (SEMA3B) as a 1,25(OH)₂D₃-stimulated gene in osteoblastic cells. Northern analysis revealed strong induction of SEMA3B mRNA by 1,25(OH)₂D₃ in MG-63, ST-2, MC3T3, and primary osteoblastic cells. Moreover, differentiation of these osteogenic cells enhanced SEMA3B gene expression. Biological effects of SEMA3B in the skeletal system have not been reported. Here, we show that osteoblast-derived SEMA3B alters global skeletal homeostasis in intact animals and osteoblast function in cell culture. Osteoblast-targeted expression of SEMA3B in mice resulted in reduced bone mineral density and aberrant trabecular structure compared with nontransgenic littermates. Histomorphometry studies indicated that this was likely due to increased osteoclast numbers and activity. Indeed, primary osteoblasts obtained from SEMA3B transgenic mice stimulated osteoclastogenesis to a greater extent than nontransgenic osteoblasts. This study establishes that SEMA3B is a 1,25(OH)₂D₃-induced gene in osteoblasts and that osteoblast-derived SEMA3B impacts skeletal biology in vitro and in vivo. Collectively, these studies support a putative role for SEMA3B as an osteoblast protein that regulates bone mass and skeletal homeostasis.

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Ligands:   Calcitriol