Macrophage iron overload promotes osteoporosis via Cxcl3- and Cxcl7-mediated paracrine signaling in ovariectomized mice.

BACKGROUND

Iron is an essential element for fundamental biological processes, but excess iron contributes to toxicity and is associated with osteoporosis in iron-overload disorders. Although iron chelators are routinely used to treat hematologic iron-overload conditions, emerging evidence suggests their potential applicability in osteoporosis treatment.

METHOD: Iron chelators were administered to ovariectomized (OVX) mice to investigate the relationship between iron overload and osteoporosis. Iron accumulation in macrophages was demonstrated through iron and F4/80 co-staining. We analyzed single-cell RNA sequencing data and utilized a Cxcr2 inhibitor to identify the pro-adipogenic factor. A single-gene knockdown approach was employed to confirm that the Cxcl3/Cxcl7-Cxcr2 paracrine signaling pathway promotes adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Finally, the effect of Cxcr2 blockade was verified in OVX mice.

RESULT: We identified iron accumulation in bone marrow-derived macrophages (BMDMs) of ovariectomized (OVX) mice, which drives BMSCs differentiation toward adipocytogenesis through Cxcl3- and Cxcl7-mediated paracrine activation of Cxcr2 on BMSCs, thereby promoting osteoporosis progression. Iron chelators reversed iron overload in BMDMs, alleviating bone marrow adiposity and bone loss.

CONCLUSION

Our findings reveal that iron overload in BMDMs acts as the novel pathogenic driver in OVX-induced bone loss, wherein the Cxcl3/Cxcl7-Cxcr2 axis serves as the critical signaling nexus between iron-laden BMDMs and adipogenic differentiation of BMSCs. Iron chelation or Cxcr2 blockade therapy may represent a potential treatment for estrogen-deficiency osteoporosis.

THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our research elucidates the mechanisms by which iron chelators and Cxcr2 inhibitors may prevent or treat estrogen-deficiency osteoporosis. Future translational research about iron chelators or Cxcr2 blockade may provide new strategies for the prevention and treatment of postmenopausal osteoporosis.