title: Osteoprotection by semaphorin 3A.
abstract: The bony skeleton is maintained by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Osteoprotegerin protects bone by inhibiting osteoclastic bone resorption, but no factor has yet been identified as a local determinant of bone mass that regulates both osteoclasts and osteoblasts. Here we show that semaphorin 3A (Sema3A) exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by inhibiting the immunoreceptor tyrosine-based activation motif (ITAM) and RhoA signalling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/β-catenin signalling pathway. The osteopenic phenotype in Sema3a−/− mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. Thus, Sema3A is a promising new therapeutic agent in bone and joint diseases.
authors.affiliation: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Mikihito
authors.initials: M
authors.lastname: Hayashi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.forename: Masahiko
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D019610:Cytoprotection / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D039942:Neuropilin-1 / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D040121:Semaphorin-3A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012886:Skull / Q000166:cytology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D039942:Neuropilin-1