p75^NTR regulates postnatal skeletal development via NGF-responsive JNK signaling

Area of Science:

• Molecular and Cellular Biology
• Skeletal Biology and Bone Homeostasis
• Developmental Biology

Background:

• p75 neurotrophin receptor (p75^NTR) is recognized for its role in skeletal development and maintaining bone health.
• Understanding the precise function of p75^NTR in bone is essential for addressing skeletal disorders.

Purpose of the Study:

• To elucidate the specific role of p75^NTR in skeletal development and bone homeostasis.
• To investigate the molecular mechanisms underlying p75^NTR's function in osteogenesis.

Main Methods:

• Characterization of skeletal phenotypes in global and mesenchyme-specific p75^NTR knockout mouse models.
• In vitro studies using bone marrow stromal cells (BMSCs) from p75^NTR-deficient mice.
• Transcriptomic profiling and functional assays to identify signaling pathways involved.

Main Results:

• Global and mesenchyme-specific deletion of p75^NTR led to growth retardation, reduced bone mass, and impaired growth plate architecture, mimicking osteoporosis.
• p75^NTR deficiency diminished osteogenic differentiation capacity, mineralization, and key osteogenic gene expression in BMSCs.
• The NGF-MAPK/AP-1 signaling axis, including JNK, KDM4B, and Dlx5, was identified as a critical downstream pathway regulated by p75^NTR.

Conclusions:

• p75^NTR plays a cell-autonomous role in regulating postnatal bone growth and osteogenesis.
• The identified NGF-p75^NTR-JNK-KDM4B-Dlx5 signaling axis is a central regulator of bone development.
• Targeting this pathway offers potential therapeutic strategies for osteoporosis and related bone diseases.