title: Sema3A regulates bone-mass accrual through sensory innervations.
abstract: Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.
authors: Department of Internal Medicine, School of Medicine, Keio University, Shinanomachi 35, Shinjyuku-ku, Tokyo 160-8582, Japan.
authors: Toru
authors: T
authors: Fukuda
authors: Shu
authors: S
authors: Takeda
authors: Ren
authors: R
authors: Xu
authors: Hiroki
authors: H
authors: Ochi
authors: Satoko
authors: S
authors: Sunamura
authors: Tsuyoshi
authors: T
authors: Sato
authors: Shinsuke
authors: S
authors: Shibata
authors: Yutaka
authors: Y
authors: Yoshida
authors: Zirong
authors: Z
authors: Gu
authors: Ayako
authors: A
authors: Kimura
authors: Chengshan
authors: C
authors: Ma
authors: Cheng
authors: C
authors: Xu
authors: Waka
authors: W
authors: Bando
authors: Koji
authors: K
authors: Fujita
authors: Kenichi
authors: K
authors: Shinomiya
authors: Takashi
authors: T
authors: Hirai
authors: Yoshinori
authors: Y
authors: Asou
authors: Mitsuhiro
authors: M
authors: Enomoto
authors: Hideyuki
authors: H
authors: Okano
authors: Atsushi
authors: A
authors: Okawa
authors: Hiroshi
authors: H
authors: Itoh
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001842:Bone and Bones / Q000033:anatomy & histology / Q000294:innervation* / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D008297:Male; D051379:Mice; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D040121:Semaphorin-3A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C488217:Sema3a protein, mouse; D040121:Semaphorin-3A
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