Osteoblast ferroptosis driven by iron overload: Implications for osteoporosis pathogenesis and FTH1/GPX4-targeted therapy.

BACKGROUND

Fractures resulting from osteoporosis are a leading cause of mortality and disability among the elderly. Ferroptosis is an emerging form of programmed cell death that occurs due to unregulated iron-dependent lipid peroxidation. Exploring the role and mechanism of ferroptosis of osteoblasts in the development of osteoporosis is of vital importance for the treatment of osteoporosis.

METHODS

Clinical samples were collected from patients requiring hip replacement surgery. Wild-type C57BL/6 mice were fed a rich-iron diet. After 1- and 2-months intervention, high-resolution μCT scanning, histopathological analysis was performed. Mouse primary bone marrow cells were treated with high iron with or without iron chelation therapy. Then, proteomics and phosphoproteomics were conducted.

RESULTS

We found a significant negative correlation between iron content and bone mineral density in clinical samples. Additionally, we demonstrated that high-iron exposure triggered ferroptosis in osteoblasts through proteomics and phosphoproteomics, thereby hindering osteogenesis and augmenting osteoclastogenesis. This cascade compromised bone microarchitecture and culminated in the development of an osteoporotic phenotype in mice and the primary bone marrow cells. Whereas iron chelation therapy may reverse these phenotypes through FTH1/GPX4 pathway.

CONCLUSION

Building upon these findings, we posit that rich-iron diet intervention in mice offers a promising model for recapitulating osteoporosis, and FTH1/GPX4 in osteoblasts emerging as a plausible therapeutic avenue for osteoporosis.