Bioactive semaphorin 3A promotes sequential formation of sensory nerve and type H vessels during in situ osteogenesis

Abstract

Introduction: Sensory nerves and vessels are critical for skeletal development and regeneration, but crosstalk between neurovascular network and mineralization are not clear. The aim of this study was to explore neurovascular changes and identify bioactive regulators during in situ osteogenesis.Method:In situ osteogenesis model was performed in male rats following Achilles tenotomy. At 3, 6 and 9 weeks after surgery, mineralization, blood vessels, sensory innervation, and bioactive regulators expression were evaluated via micro-computed tomography, immunofluorescent staining, histology and reverse transcriptase-polymerase chain reaction analyses.Result: In the process of in situ osteogenesis, the mineral density increased with time, and the locations of minerals, nerves and blood vessels were highly correlated at each time point. The highest density of sensory nerve was observed in the experimental group at the 3rd week, and then gradually decreased with time, but still higher than that in the sham control group. Among many regulatory factors, semaphorin 3A (Sema3A) was highly expressed in experimental model and its expression was temporally sequential and spatially correlated sensory nerve.Conclusion: The present study showes that during in situ osteogenesis, innervation and angiogenesis are highly correlated, and Sema3A is associated with the position and expression of the sensory nerve.

Expression of semaphorin‐3A in the joint and role in osteoarthritis

“…Sema-3A is needed for normal patterning and growth of nerves 33 and was shown to play a role in bone innervation. 21,34 It was recently shown that sema-3A is associated with sensory nerves and type H vessels during in situ osteogenesis, 35 confirming the close interaction between sema-3A F I G U R E 2 Changes in semaphorin-3A (sema-3A) expression in OA mouse knee joints. Osteoarthritis was induced by mechanical joint loading (MJL) at 9N (B) and 11N (C).…”

“…Sema‐3A is needed for normal patterning and growth of nerves 33 and was shown to play a role in bone innervation 21,34 . It was recently shown that sema‐3A is associated with sensory nerves and type H vessels during in situ osteogenesis, 35 confirming the close interaction between sema‐3A and sensory nerves. Our data show that sema‐3A expression is upregulated during OA in those highly innervated joint tissues.…”

Emerging roles of nerve‐bone axis in modulating skeletal system

“…Sema3A is closely associated with the position and expression of sensory nerves and vasculatures during osteogenesis. 157 Interestingly, it was reported that neural cell-derived Sema3A was more important in regulating bone mass than the osteoblast-derived Sema3A in the neonatal stage. 150 Researchers found that mice lacking Sema3A in osteoblasts showed normal bone mass, even though Sema3A expression in bone declined considerably.…”

“…As is known, Sema3A is an autocrine factor and a fundamental component of proper neural development. Sema3A is closely associated with the position and expression of sensory nerves and vasculatures during osteogenesis 157 . Interestingly, it was reported that neural cell‐derived Sema3A was more important in regulating bone mass than the osteoblast‐derived Sema3A in the neonatal stage 150 .…”