Elevated calcitonin gene-related peptide expression through prostaglandin E2-EP4 receptor pathway in promoting proliferative periosteum formation in primary hypertrophic osteoarthropathy

Background: Periosteosis is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO). Increased level of prostaglandin E2 (PGE2) is the pathogenesis of PHO. PGE2 has been shown to bind its EP4 receptor in sensory nerves to stimulate bone formation. Sensory neuropeptide calcitonin gene-related peptide (CGRP), richer in the periosteum, has been revealed to promote osteogenic differentiation of periosteum-derived stem cells (PDSCs) and contributed to periosteum proliferation at peripheral cortical sites. The study hypothesized that CGRP might have a role in regulating proliferative periosteum formation in PHO through the PGE2/EP4 receptor pathway. Methods: , PDSCs and bone mesenchymal stem cells (BMSCs) were isolated from the normal rats and treated with PGE2 to evaluate and compare osteogenic differentiation. Results: study revealed that PGE2 treatment upregulated the expression of CGRP throughout the osteogenesis differentiation in PDSCs. Conclusion: evidenced elevated CGRP expression through PGE2/EP4 axis promoted proliferative periosteal formation, suggesting that CGRP might be a potential target for PGE2-induced periosteosis treatment, providing new insight into potential therapies for PHO patients. Translational potential of this study: This study identifies CGRP as a key mediator in PGE2/EP4-induced periosteal bone formation, revealing its critical role in the pathogenesis of periosteosis in primary hypertrophic osteoarthropathy (PHO). Targeting the CGRP signaling pathway offers a promising therapeutic strategy to modulate aberrant periosteal proliferation and bone remodeling in PHO patients. These findings pave the way for developing novel treatments aimed at inhibiting CGRP activity to alleviate periosteal hyperplasia and improve clinical outcomes in PHO.