Osteoprotection by semaphorin 3A
Osteoprotection by semaphorin 3A
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DOI：
10.1038/nature11000
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发表时间：
2012-05-03
期刊：
影响因子：
64.8
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Hayashi, Mikihito;Nakashima, Tomoki;Takayanagi, Hiroshi
除了激素活性之外，骨骨架还由调节骨形成成骨细胞和骨吸收破骨细胞的局部因素维持。骨保护素通过抑制骨细胞的骨吸收来保护骨，但是还没有一种因子被确定为调节破骨细胞和成骨细胞的骨量的局部决定因素。在这里，我们表明，脑信号蛋白3A（Sema 3A）发挥骨保护作用，抑制骨细胞骨吸收和增加成骨细胞骨形成。Sema 3A与神经纤毛蛋白-1（Nrp 1）的结合通过抑制免疫受体酪氨酸激活基序（ITAM）和RhoA信号通路抑制核因子-κ B配体受体激活剂（RANKL）诱导的破骨细胞分化。此外，Sema 3A和Nrp 1结合刺激成骨细胞和抑制脂肪细胞分化通过经典的Wnt/β-连环蛋白信号通路。Sema 3a（-/-）小鼠的骨质减少表型被Nrp 1的Sema 3A结合位点被遗传破坏的小鼠重演。在小鼠中静脉内施用Sema 3A增加了骨体积并加速了骨再生。因此，Sema 3A是一种很有前途的新的骨关节疾病治疗剂。
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-kappa B 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/beta-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.