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The p75 neurotrophin receptor regulates the skeletal stem cell niche through sensory innervation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263602 | GEO | 2025/08/27

REPOSITORIES: GEO

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Project description:This study aimed to quantify the regulation of transcripts in the hairy skin of the back of adult rats in the condition of loss of sensory and autonomic (sympathetic) innervation (i.e., denervated). Denervated skin has reduced wound healing capacity, reduced proliferation of epidermal progenitor cells, and also expresses factors that regulate ingrowth of sensory and sympathetic axons from neighboring regions of innervated skin. It was expected that this quantification f transcript regulation would offer insight into the general and specific mechanisms that may contribute to these important biological processes. All animals were adult (200-250g) Sprague-Dawley female rats. Three conditions were examined. Groups were naive (n=6), 7-day denervated skin (n=5), and 14-day (n=5) denervated skin. Denervation preparations: Full-thickness incision along long-axis of the body 1cm to right of midline (to avoid injuring skin to be sampled). Incision was centered rostro-caudally on the T13 (thoracic 13) costo-vertebral angle so as to allow access to the T9-L2 (lumbar 2) cutaneous nerves. Skin was reflected to the left and the left T9, T10, L1, and L2 dorsal and lateral cutaneous nerves were isolated, ligated with 7-0 monofilament suture close to their exit from the body wall, and transected. Approximately 5mm of the distal portion of the nerve was resected. The T11 nerves were left unperturbed and were not isolated from the surrounding fascia. This generated two strips of skin that were devoid of sensory and autonomic innervation (those strips served by the T9 and T10 nerves, and by the L1 and L2 nerves). Between these denervated strips of skin was a strip of skin that retained the sensory and autonomic axons supplied by T11 nerves. The denervated zones were identified by mapping the cutaneous trunk muscle (CTM) reflex (see Petruska-JC et al. (2013) Journal of Comparative Neurology; Diamond-J et al., (1992) J Neuroscience), and the border marked with pen and remarked every few days. The samples were taken from the rostral (T9/10) denervated zone. Samples from naive animals (no denervation) were taken from the same region, using the dorsal cutaneous nerves as registration landmarks. Animals displayed no signs of overgrooming of the denervated skin. Because the CTM inserts onto the dermis of this region of skin, samples necessarily include both skin and underlying CTM (which is innervated from another source so was not denervated in the experiment).

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The p75 neurotrophin receptor regulates the skeletal stem cell niche through sensory innervation

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