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Boosting TrkA+ Sensory Nerve-to-Bone Interactions Enhances Calvarial Bone Repair and Hedgehog Signaling Activation

ABSTRACT: The neuroregulatory effects of sensory nerves in bone repair have recently begun to be elucidated, principally through loss of function studies. However, the potential therapeutic efficacy of boosting nerve-to-bone interactions, as well as the elucidation of downstream signaling pathways remains poorly studied. Here, two parallel approaches were utilized to enhance sensory nerve-to-bone interactions using a mouse calvarial bone defect model system. Pharmacologic activation of TrkA with gambogic amide induced bone-associated nerve ingrowth and markedly improved calvarial bone healing. Single-cell RNA sequencing analysis of cells derived from the defect site revealed shifts in cluster proportions, with enrichment of immune cell populations in TrkA agonist-treated mice. Within the skeletal cell lineage, TrkA agonism enhanced osteoblast differentiation while suppressing fibroblastic differentiation. Pathway analysis showed increased activity of Hedgehog, Wnt, BMP, and other osteogenic pathways. Further investigation of intercellular communication identified elevated Hedgehog signaling pathway specifically from DRG neurons. In summary, activation of TrkA-positive sensory nerves stimulates hedgehog pathway activity in local mesenchymal stem and progenitor cells, promoting osteoblast differentiation and bone formation. Our study thus elucidates signaling mechanisms underlying neurogenically-enhanced bone repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE266598 | GEO | 2026/02/05

REPOSITORIES: GEO

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Project description:Low bone mass is strongly associated with multiple neurologic diseases such as Alzheimer’s disease (AD), however it remains unclear if this represents direct specific biologic sequalae of the primary disease process or rather a non-specific finding attributable to alterations in behavior and activity. The recent discovery of skeletal stem cells (SSCs) generating bone forming osteoblasts offers a new opportunity to understand both AD effects on bone and broader neural effects on bone by determining whether there are neural contributions to the SSC niche. Deletion of p75NTR (an essential neurotrophin receptor) was used to probe the contributions of peripheral innervation to the SSC niche. p75NTR deletion either broadly in neurons (p75NTRsyn1 mice) or more specifically in sensory nerves (p75NTRadv mice) but not osteogenic cells (p75NTRocn and p75NTRprx1 mice) or sympathetic nerves (p75NTRth mice), led to decrease in sensory innervation, impaired SSC homeostasis, and bone loss. Consistent with this, pharmacological sensory denervation resulted in a decrease in SSC numbers. More directly, wild-type SSCs transplanted orthotopically into the bones of p75NTRadv host mice with reduced sensory innervation displayed an impaired osteogenic capability, indicating that sensory nerves comprise part of the SSC niche. Decreased sensory innervation in p75NTRadv mice further impaired fracture healing by suppressing SSC expansion. Transcriptomic profiling to identify sensory nerve derived mediators of the SSC niche effect identified that p75NTR regulates expression of Osteopontin (SPP1) in neurons of the dorsal root ganglion (DRG), and SPP1 in turn acts as to promote SSC self-renewal and osteogenic capacity. Lastly, this p75NTR-SPP1 axis is impaired in AD mice, providing a new, direct mechanism for osteopenia in AD both impacting basal bone turnover and fracture repair. Altogether, our findings newly establish sensory nerves as a key component of SSC niche that is disrupted in AD, providing new therapeutic opportunities to augment SSC function to treat bone disorders such as Alzheimer’s associated osteopenia.

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Boosting TrkA+ Sensory Nerve-to-Bone Interactions Enhances Calvarial Bone Repair and Hedgehog Signaling Activation

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