Sensory Nerves May Be Key for Osteoporosis

For the first time, investigators demonstrate that sensory nerves have an essential role in bone remodeling. In particular, semaphorin 3A (Sema3A) regulates bone remodeling by modulating sensory nerve development. It does this without directly acting on osteoblasts.

Toru Fukuda and colleagues from Keio University in Tokyo published the results of their knockout mouse study in Nature.¹ Their research in bone remodeling builds on their earlier demonstration that Sema3A is critical for the normal development of sensory neurons in vivo. They have previously shown that Sema3A knockout mice exhibit neuronal abnormalities such as problems with olfactory development.

The current study was designed to address the role of Sema3A in bone remodeling. To that end, the investigators created four additional strains of mice. They created two strains of mice that were osteoblast-specific Sema3A-deficient (Sema3a_col1^-/- and Sema3a_osx^-/-) and found that these mice have normal bone mass despite the substantial decrease of Sema3A in bone.

The authors also created two strains of mice that were neuron-specific Sema3A-deficient (Sema3a_synapsin^-/- and Sema3a_{nestin ^-/-}). These mice have the low bone mass that is characteristic of the Sema3a^_-/- mice. The difference between the mouse strains suggests that neuron-derived and not bone-derived Sema3A is responsible for the bone abnormalities.

Sema3a_synapsin^-/- and Sema3a_nestin^-/- mice exhibit the same abnormal neuronal development as that seen in the Sema3_a^-/- mice, indicating that the Sema3A produced by neurons regulates neuronal development in an autocrine manner. The authors also found that Sema3a_{synapsin^-/–} mice had significantly fewer sensory innervations of trabecular bone. In contrast, sympathetic innervations of trabecular bone were unchanged in these mice.

When the investigators ablated sensory nerves in wild-type mice, they were able to decrease bone mass. In contrast, ablation did not reduce the low bone mass seen in Sema3a_nestin^-/- mice any further.

“These results demonstrate an essential role of sensory nerves in bone metabolism,” wrote coauthor Shu Takeda, MD, PhD, of Keio University in an e-mail to The Rheumatologist. The authors proposed in their paper that Sema3A does this by modulating sensory nerve projections into the bone.

When asked about the implications for weight-bearing exercise, Dr. Takeda responded: “It is possible that weight-bearing exercise increases bone formation by affecting sensory nerves, as you may hypothesize. Currently there is no experimental evidence, but it is under investigation.”

Dr. Pullen is a medical writer based in the Chicago area.

Reference

1. Fukuda T, Takeda S, Xu R, et al. Sema3A regulates bone-mass accrual through sensory innervations. Nature. 2013;497:490-493.