p75NTR regulates postnatal skeletal development via NGF-responsive JNK signaling

p75^NTR 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 <i>p75</i> ^<i>NTR</i> knockout mouse models. Global deletion of <i>p75</i> ^<i>NTR</i> 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 <i>p75</i> ^<i>NTR</i> 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 <i>p75</i> ^<i>NTR</i> -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 <i>p75</i> ^<i>NTR</i> -deficient BMSCs. Functional studies demonstrated that loss of <i>p75</i> ^<i>NTR</i> reduced JNK pathway activation and downstream epigenetic regulators, including <i>Kdm4b</i> and its target gene <i>Dlx5</i>. Overexpression of <i>Kdm4b</i> rescued mineralization defects and restored osteogenic gene expression in <i>p75</i> ^<i>NTR</i> -deficient BMSCs, establishing a mechanistic link between p75^NTR signaling and osteoblast differentiation. These findings define the NGF-p75^NTR-JNK-KDM4B<i>-Dlx5</i> axis as a central regulatory pathway in postnatal bone growth and osteogenesis. Given the critical role of p75^NTR 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.