Sympathetic cholinergic nerve fibres promote BMSC differentiation into osteoblasts via NRTN secretion: a potential treatment for osteoporosis.

BACKGROUND: Peripheral nerves within the bone actively participate in bone remodelling by secreting various bioactive molecules, and dysfunction or changes in their abundance greatly contribute to the onset of osteoporosis. While it is well established that sympathetic adrenergic nerve fibres reduce bone mass and contribute to osteoporosis, the role of sympathetic cholinergic signalling in this condition is still poorly understood. We aimed to investigate whether sympathetic cholinergic nerve fibres influence osteoporosis through the secretion of neurturin (NRTN). METHODS: A mouse model of osteoporosis was established via bilateral ovariectomy (OVX). Differences in cholinergic signalling and NRTN expression levels between sham-operated control mice and OVX mice were assessed using methods such as quantitative real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and immunofluorescence staining. The effects of NRTN on bone mass and bone formation were examined in vivo through micro-computed tomography analysis, bone morphometric analysis, histological analysis, and immunohistochemistry staining. In vitro, clone formation assay, tartrate-resistant acid phosphatase staining, alkaline phosphatase staining, and alizarin red S staining were employed to validate the impacts of NRTN on osteoblast proliferation, osteoclast differentiation, and osteoblast differentiation. RESULTS: Sympathetic cholinergic signalling was diminished in OVX mice, coinciding with a decrease in the neurotrophic factor, NRTN, which is secreted by sympathetic cholinergic nerve endings. NRTN treatment resulted in a dose-dependent increase in bone mass in OVX mice. Subsequent investigations confirmed that NRTN promotes bone formation in vivo and enhances the differentiation of bone marrow mesenchymal stem cells into osteoblasts in vitro. CONCLUSIONS: Our results suggest that sympathetic cholinergic nerve fibres promote bone mass through NRTN secretion, providing new insights into potential therapeutic strategies for osteoporosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13018-025-05944-4.