p75NTR regulates postnatal skeletal development via NGF-responsive JNK signaling

Abstract

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 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 p75^NTR signaling and osteoblast differentiation. These findings define the NGF–p75^NTR–JNK–KDM4B–Dlx5 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.