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.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Notably, mutations in FGF8, FGFR1 or SEMA3A might not only cause GnRH deficiency but also directly affect bone. 153,239 We recommend a baseline bone density measurement in all patients with CHH at final height and after 2 years of treatment. To date, insufficient evidence exists to use the WHO-FRAX risk calculator 240 in this population of patients.…”

Bone cell communication factors and Semaphorins

“…In a recent study, Sema3A was shown to be predominantly produced by osteoblast lineage cells, whereas the receptor complex was expressed both on osteoblast lineage cells and osteoclast precursor cells. 39 It has been reported that Plexin-A1 promotes osteoclast differentiation by activating ITAM signaling through the formation of the Plexin-A1 -TREM-2 -DAP12 complex. 34 The binding of Sema3A to Neuropilin-1 resulted in abrogation of the differentiation capacity of osteoclast precursor cells by sequestering Plexin-A1 from TREM2 so as to suppress ITAM signaling.…”

“…It was clearly demonstrated that the treatment with the Sema4D-specific neutralizing antibody and recombinant Sema3A not only effectively protected against bone loss in mouse model of osteoporosis, but also restored the lost bone by increasing bone formation. 28,39 Considering the involvement of Sema4D and Sema3A in the pathological setting, including cancer progression and autoimmune diseases, the blocking of Sema4D or treatment with Sema3A promise as a strategy for the design of agents with pleiotropic effects on bone loss associated with autoimmune diseases and bone tumors.…”

“…39 Furthermore, knock-in mice in which the Nrp1 gene was replaced by mutant Nrp1 35 future studies using osteoblast lineage-specific Sema3a − / − conditional knockout mice will be informative.…”

“…However, a recent study reported that a substantial anti-osteoclastogenic effect was observed in the conditioned medium of OPG-deficient calvarial cells and they identified another Semaphorin family member Sema3A as the osteoblast-secreted inhibitors of osteoclast differentiation by mass spectrometry. 39 Sema3A, which is secreted protein, is the first identified vertebral Semaphorin and has been the most extensively studied in the nervous system, but now is also recognized to be involved in multiple physiological and pathological processes. Recent reports demonstrated that the Sema3A suppresses the onset of autoimmune diseases such as SLE, rheumatoid arthritis and multiple myeloma, as well as tumor progression.…”