p75 regulates postnatal skeletal development via NGF-responsive JNK signaling.

p75 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 knockout mouse models. Global deletion of 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 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 -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 -deficient BMSCs. Functional studies demonstrated that loss of reduced JNK pathway activation and downstream epigenetic regulators, including and its target gene . Overexpression of rescued mineralization defects and restored osteogenic gene expression in -deficient BMSCs, establishing a mechanistic link between p75 signaling and osteoblast differentiation. These findings define the NGF-p75-JNK-KDM4B axis as a central regulatory pathway in postnatal bone growth and osteogenesis. Given the critical role of p75 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.