Semaphorin 3A的骨保护作用

来源：仪方生物 www.yeslab.com

骨骼骨架是通过体内成骨细胞和骨吸收的破骨细胞来维持的，外加荷尔蒙的作用。护骨因子抑制破骨细胞的骨吸收从而起着护骨作用，但是还没有找到确切的调控成骨和破骨细胞而维持骨量的因子。本项研究发现semaphorin 3A（sema3A）起着骨保护作用，不但能够抑制破骨细胞的作用，还起着增加成骨细胞的成骨功能。Sema3A与神经纤毛蛋白-1（Nrp1）结合后抑制抑制免疫受体酪氨酸活化基序（ITAM）和RhoA信号转导通路，从而抑制核因子kB配体（RANKL）诱导的破骨细胞分化活性。此外，Sema3A和Nrp1结合后通过Wnt/β-连环蛋白信号通路激发成骨细胞并抑制脂肪细胞分化。在Sema3A突变小鼠中的骨质疏松表型概括为Sema3A结合位点Nrp1遗传变化。静脉Sema3A的管理能够增加骨量并加快骨组织生长，Sema3A是骨关节疾病中很有前途的治疗剂。

Mikihito Hayashi1,2,3, Tomoki Nakashima1,2,3, Masahiko Taniguchi4, Tatsuhiko Kodama5, Atsushi Kumanogoh6,7
& Hiroshi Takayanagi1,2,3,8
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-kB 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/b-catenin signalling pathway. The osteopenic phenotype in Sema3a2/2 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.