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. We explored the regulatory mechanisms of CGRP in proliferative periosteosis of PGE2 in vivo and in vitro . In vivo , PGE2 at 3 mg/kg/day or vehicle was given by daily subcutaneous injection along the periosteum at bilateral lower extremities to male rats for 30 days. After sacrificing the rats, tibiae and femurs were collected to conduct micro-CT, histopathological, and bone histomorphometric analysis. PDSCs were isolated from PGE2-treated and vehicle-treated rats to analyze osteogenic differentiation. In vitro , PDSCs and bone mesenchymal stem cells (BMSCs) were isolated from the normal rats and treated with PGE2 to evaluate and compare osteogenic differentiation. PGE2 administration induced significant bone gain phenotype with higher cortical areas and cortical and trabecular bone volumes at the microarchitectural level. Histological and molecular analysis of the periosteum isolated from the PGE2-treated rats revealed that high CGRP expression in the PGE2/EP4 pathway promoted osteogenesis and mineralization in the peripheral cortex of the femur. Furthermore, in vitro study revealed that PGE2 treatment upregulated the expression of CGRP throughout the osteogenesis differentiation in PDSCs. Both in vivo and in vitro 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. 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.
Pang et al. (Sat,) studied this question.