The dual roles of EGFR signaling in skeletal homeostasis: from bone remodeling to cartilage metabolism and differentiated targeting strategies.

The epidermal growth factor receptor (EGFR), a key tyrosine kinase of the ErbB family, regulates cell fate and tissue homeostasis in the skeletal system through complex downstream signaling networks, including the MAPK/ERK, PI3K/Akt, and NF-κB pathways. The balance between its physiological and pathological functions is critical for maintaining osteoprogenitor pools and articular cartilage integrity; however, yet how to selectively target EGFR in skeletal diseases remains poorly understood. To address this research gap, This review summarizes the dual roles of EGFR in osteoporosis (OP) and osteoarthritis (OA). We summarize its involvement in bone remodeling and cartilage degradation, compile evidence from network pharmacology linking EGFR to pharmacological modulators, and provide structural insights into its activation and inhibition via in silico molecular docking. Furthermore, this review highlights several unresolved questions: the cell-type-specific and spatiotemporal mapping of EGFR activation, the precise mechanisms of its allosteric modulation, and the development of tissue-targeted, non-oncological EGFR delivery systems. Addressing these gaps will be important for developing precision-based therapeutic strategies for skeletal degeneration.