p75NTR regulates postnatal skeletal development via NGF-responsive JNK signaling.

p75NTR has emerged as a key regulator of skeletal development and bone homeostasis. To define its role, we characterized skeletal phenotypes in global and mesenchyme-specific p75 NTR knockout mouse models. Global deletion of p75 NTR resulted in postnatal growth retardation, decreased trabecular and cortical bone mass, and impaired growth plate architecture-hallmarks of an osteoporotic phenotype that persisted into adulthood. Conditional deletion of p75 NTR in mesenchymal progenitor cells using Prx1-Cre recapitulated these skeletal deficits, confirming a cell-autonomous role in bone development. In vitro, bone marrow stromal cells (BMSCs) derived from p75 NTR -deficient mouse exhibited diminished osteogenic differentiation capacity, reduced mineralization, and downregulation of key osteogenic genes. Transcriptomic profiling revealed significant suppression of the NGF-MAPK/AP-1 signaling axis in p75 NTR -deficient BMSCs. Functional studies demonstrated that loss of p75 NTR reduced JNK pathway activation and downstream epigenetic regulators, including Kdm4b and its target gene Dlx5. Overexpression of Kdm4b rescued mineralization defects and restored osteogenic gene expression in p75 NTR -deficient BMSCs, establishing a mechanistic link between p75NTR signaling and osteoblast differentiation. These findings define the NGF-p75NTR-JNK-KDM4B-Dlx5 axis as a central regulatory pathway in postnatal bone growth and osteogenesis. Given the critical role of p75NTR in skeletal development and bone homeostasis, targeted modulation of this signaling cascade may represent a promising therapeutic approach for treating osteoporosis and other bone disorders.