Sema3A regulates bone-mass accrual through.pdfVIP

LETTER doi:10.1038/nature12115 Sema3A regulates bone-mass accrual through sensory innervations Toru Fukuda1*, Shu Takeda1*, Ren Xu2,3*, Hiroki Ochi1, Satoko Sunamura1, Tsuyoshi Sato4, Shinsuke Shibata5, Yutaka Yoshida6, Zirong Gu6, Ayako Kimura2,7, Chengshan Ma2,3, Cheng Xu2,3, Waka Bando8, Koji Fujita2,3, Kenichi Shinomiya2, Takashi Hirai2, Yoshinori Asou2, Mitsuhiro Enomoto2, Hideyuki Okano5, Atsushi Okawa2,3 Hiroshi Itoh8 Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance1–5. Previous studies have demonstrated that Sema3a2/2 mice have multiple developmental defects due to abnormal neuronal innervations6,7. 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, Sema3a2/2 mice had a low bone mass due to decreased bone formation. However, osteoblast- specific Sema3A-deficientmice (Sema3acol1 2/2 andSema3aosx 2/2mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A inneurons (Sema3asynapsin 2/2andSema3anestin 2/2mice)had lowbone mass, similar to Sema3a2/2 mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities inde- pendent of the local effect of Sema3A inbone. Indeed, thenumberof sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin 2/2 mice, whereas sympathetic innervations of trabecular bonewereunchanged.Moreover, ablating sensorynerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin 2/2 mice further, supporting the essential role of the sensory nervous system in normal bone home- ostasis. Finally, neuronal abnormalities in Sema3a2/2mice, such as olfactory development, were identified in Sema3asynasin 2/2 mice, demonstrating that neuron-derived Sema3A contributes to the abnormalneur