Neuronal receptor remodeling in the aging periosteum: From single-cell atlases to regenerative targets

The periosteum is the most densely innervated compartment of the skeleton and harbors periosteal stem cells expressing a broad repertoire of neuronal receptors traditionally associated with the nervous system. This narrative review aimed to map the neuronal receptor landscape of the periosteum and its age-dependent remodeling, and to evaluate the therapeutic implications of these receptors for age-related skeletal disorders. Literature was identified using a structured, PRISMA-informed search strategy across PubMed/MEDLINE, Web of Science, Scopus, and Embase from database inception. Eligible studies addressed neuronal receptor expression or signaling in periosteal tissue, periosteal stem and progenitor cells, or bone. Additionally, an exploratory reanalysis of the publicly available GSE297256 single-cell transcriptomic dataset was performed to contextualize the literature synthesis; no unpublished data were included. The literature synthesis delineated seven major neuronal receptor families in periosteal homeostasis: semaphorin-neuropilin, neurotrophin-Trk, Slit-Robo, adrenergic, cannabinoid, purinergic, and sensory neuropeptide systems. Restricting the analysis to bona fide neuronal receptors, 29 receptor genes were actively transcribed in periosteal stem cells, with neuropilin 2 (Nrp2) ranking highest by a composite score integrating expression magnitude, detection frequency, and cell-type specificity. In exploratory cell-level analysis, Nrp2 expression showed a progressive age-associated increase from young (log1p mean 1.35) to middle-aged (1.85) to old (2.70) mice, concomitant with a decline of Postn-expressing Osteo-X progenitors and activation of stress-response genes (Mt1, Mt2, Gadd45b, and Cebpd), and was associated with dysregulation of the axon guidance ligand Slit2, downregulation of osteocalcin-associated genes (Bglap and Bglap2), and predicted upstream regulation by the vitamin D receptor, implicating a vitamin D receptor-Nrp2 axis in periosteal aging. Age-related periosteal dysfunction, including cambium layer thinning, progenitor decline, and impaired progenitor-immune crosstalk, paralleled this receptor dysregulation. Neuronal receptor modulation, including Bdnf-TrkB, Sema3a-Nrp1, and Nrp2-targeted strategies, emerges as a promising multimodal approach for skeletal regeneration and aging intervention, warranting functional and clinical validation.