Epiregulin ameliorates ovariectomy-induced bone loss through orchestrating the differentiation of osteoblasts and osteoclasts.

Summary

Epiregulin promotes osteoblastogenesis and suppresses adipogenesis via EGFR-dependent mTORC1 inactivation and reduces osteoclastogenesis by downregulating RANKL, reversing OVX-induced trabecular bone loss. This identifies epiregulin–EGFR–mTORC1 as a mechanistic axis governing bone remodeling with therapeutic potential.

Key Findings

• Epiregulin expression rises during osteogenesis and falls during adipogenesis in BMSCs.
• Epiregulin enhances osteoblast differentiation and inhibits adipocyte differentiation via EGFR.
• EGFR silencing abrogates epiregulin’s effects, indicating EGFR indispensability.
• Mechanistically, epiregulin–EGFR inactivates mTORC1; epiregulin downregulates RANKL and suppresses osteoclast differentiation.
• Recombinant epiregulin treatment in OVX mice increases bone formation, reduces resorption, and ameliorates cancellous bone loss.

Clinical Implications

Targeting the epiregulin–EGFR–mTORC1 axis may offer dual anabolic–antiresorptive activity. Translational development will require careful safety profiling due to EGFR signaling in other tissues and malignancies.

Limitations

• Preclinical study without human data; long-term safety and dosing remain unknown.
• Potential off-target effects given EGFR roles in multiple tissues and cancer biology.

Future Directions

Evaluate EREG agonism/antagonism strategies in larger animal models; test combination with standard osteoporosis agents; delineate safety in EGFR-rich tissues and neoplastic contexts.