The Impact of Osteocytic Iron Overload on Postmenopausal Osteoporosis through Inhibiting the Osteoblast Osteogenesis via INSL3 Signaling Pathway
LIU Shaoqiang1, QIU Xue2, LI Ruidong1, WANG Hao1*
This study aimed to explore whether iron overload in postmenopausal osteoporosis condition can induce the ferroptosis and functional changes of osteocyte, thereby affecting its regulation of bone physiology and leading to osteoporosis, and to clarify the underlying mechanisms. An in vitro model of osteocytic iron over load was established, and co-culture experiments were conducted to examine the effects of osteocyte iron overload on the osteoblast osteogenesis. RNA-Seq was used to identify potential signaling pathways followed by validation. In vivo studies utilized ovariectomized mice to simulate postmenopausal osteoporosis. Cortex and trabecula were evaluated using histological and imaging techniques, along with measurements of ferroptosis-related proteins. In vitro, iron overload could induce the ferroptosis of MLO-Y4 cells. Co-culture results showed that osteocytic iron overload reduced the osteogenic mineralization ability of MC3T3-E1 cells and suppressed the expression of osteogenic proteins. Transcriptomic sequencing revealed that iron overload of MLO-Y4 cells inhibited the INSL3 pathway in MC3T3-E1 cells. ELISA detected increased inflammatory cytokines secreted from MLO-Y4 cells under iron overload. In vivo, ovariectomized mice exhibited thinner bone cortex and more osteoporotic trabecula. Immu nohistochemistry indicated higher ferroptosis level, while deferoxamine intervention alleviated osteoporosis. Osteo cytic iron overload can induce ferroptosis, which suppresses the INSL3 signaling pathway in osteoblasts, inhibiting osteogenesis and promoting the progression of postmenopausal osteoporosis.
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