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.