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.

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

“…This evolutionarily primitive neuron functions bidirectionally-its distal axon terminal not only transduces and transmits pain, but it also releases electrical and paracrine chemical signals that maintain tissue homeostasis. C-fiber trophic signals are critical for the integrity of skin and bone for instance [1,2]. Other C-fiber paracrine secretions modulate tissue responses to injury or threat.…”

Netrin‐4 derived from murine vascular endothelial cells inhibits osteoclast differentiation in vitro and prevents bone loss in vivo

“…The plastic blocks were trimmed and 4 or 7-lm thick sections were prepared with a RM2255 (Leica Microsystems). Undecalcified sections of the lumbar vertebrae were stained for von Kossa, Toluidine Blue and TRAP staining, as previously described [6]. Static and dynamic histomorphometric analyses were performed using OsteoMeasure Analysis System (OsteoMetrics) following nomenclature defined by the American Society for Bone and Mineral Research.…”

“…Very recently, we showed that the sensory nerve plays a core role in bone remodeling [6]. Vascularization supplies various tissues including bone with oxygen, nutrients, hormones and cytokines, suggesting that angiogenesis is vital to the skeletal development and bone remodeling [7,8].…”

Functional Roles of Netrin-1 in Osteoblast Differentiation

“…Previous studies have demonstrated that neural and vascular regulation factors, such as semaphorins and netrins, orchestrate bone metabolism. We have demonstrated that semaphorin 3A, which is a diffusible axonal chemorepellent that has an important role in axon guidance, regulates bone remodeling indirectly by modulating sensory nerve development and also found that it enhances the elongation of dendrite in osteocytes (4,5). Semaphorin 3A exerts an osteoprotective effect by both suppressing bone resorption and increasing bone formation (6).…”