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<p>Cadmium (Cd) exposure causes osteoporosis by primarily inhibiting osteogenic differentiation. However, the specific epigenetic mechanisms, particularly the role of miRNAs, remain to be elucidated. Here, our study reveals the critical function of the miR-155/SMAD5 axis in this pathological process. In vivo, female Sprague–Dawley rats were randomly assigned to four groups and treated for 16 weeks: control, 25, 50, and 100&#xa0;mg/L cadmium chloride (CdCl<sub>2</sub>). In vitro, primary bone marrow mesenchymal stem cells (BMSCs) from rats were treated with 0, 25, 50, 100&#xa0;mg/L CdCl<sub>2</sub>, and 0, 0.46, 0.92&#xa0;mg/L CdCl<sub>2</sub> for primary human BMSCs (hBMSCs). We demonstrated that Cd exposure induced a dose-dependent trabecular bone damage and reduced serum bone formation markers in rats. Cd suppressed osteogenic differentiation in both BMSCs and hBMSCs, as evidenced by inhibited calcium nodules formation and downregulation of the bone formation markers (Runx2, ALP, and Osterix). Mechanistically, we discovered that miR-155 expression was significantly upregulated, accompanied by the downregulation of its target, Smad5, both in vivo and in vitro. Notably, the miR-155 inhibitor effectively rescued Cd-induced impairments by restoring SMAD5 expression, enhancing ALP activity, and promoting calcium nodule formation. In conclusion, our findings revealed a novel mechanism by which Cd inhibited osteogenic differentiation via the miR-155/SMAD5 pathway, providing new insights into epigenetic regulation of Cd-induced osteoporosis and potential therapeutic targets for controlling Cd-related bone damage.</p> Graphical abstract <p></p>

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Cadmium causes osteoporosis by osteogenic differentiation inhibition via miR-155/SMAD5 pathway: evidence from in vivo and in vitro studies

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Lifen Mo,
  • Lijun Mo,
  • Youkun Hu,
  • Siyu Wan,
  • Meng Zhou,
  • Wei Zhu,
  • Guangyu Yang,
  • Qinzhi Wei,
  • Jia Song,
  • Xingfen Yang

摘要

Cadmium (Cd) exposure causes osteoporosis by primarily inhibiting osteogenic differentiation. However, the specific epigenetic mechanisms, particularly the role of miRNAs, remain to be elucidated. Here, our study reveals the critical function of the miR-155/SMAD5 axis in this pathological process. In vivo, female Sprague–Dawley rats were randomly assigned to four groups and treated for 16 weeks: control, 25, 50, and 100 mg/L cadmium chloride (CdCl2). In vitro, primary bone marrow mesenchymal stem cells (BMSCs) from rats were treated with 0, 25, 50, 100 mg/L CdCl2, and 0, 0.46, 0.92 mg/L CdCl2 for primary human BMSCs (hBMSCs). We demonstrated that Cd exposure induced a dose-dependent trabecular bone damage and reduced serum bone formation markers in rats. Cd suppressed osteogenic differentiation in both BMSCs and hBMSCs, as evidenced by inhibited calcium nodules formation and downregulation of the bone formation markers (Runx2, ALP, and Osterix). Mechanistically, we discovered that miR-155 expression was significantly upregulated, accompanied by the downregulation of its target, Smad5, both in vivo and in vitro. Notably, the miR-155 inhibitor effectively rescued Cd-induced impairments by restoring SMAD5 expression, enhancing ALP activity, and promoting calcium nodule formation. In conclusion, our findings revealed a novel mechanism by which Cd inhibited osteogenic differentiation via the miR-155/SMAD5 pathway, providing new insights into epigenetic regulation of Cd-induced osteoporosis and potential therapeutic targets for controlling Cd-related bone damage.

Graphical abstract