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<p>Mitochondrial regulation in mesenchymal stem cells (MSCs) serves as a critical determinant of bone formation and skeletal homeostasis. While dietary nitrate and its transporter Sialin are implicated in systemic homeostasis, their specific roles in MSCs' function remain unclear. Here, we demonstrate that Sialin deficiency impairs MSCs' function and disrupts bone homeostasis. Gain- and loss-of-function studies reveal that Sialin localizes to the mitochondrial membrane and promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity. Mechanistically, Sialin recruits pSTAT3<sup>S727</sup> to mitochondria, forming a functional complex that activates mitochondrial bioenergy and stabilizes bone remodeling. Notably, dietary nitrate restores Sialin expression in aged mice, thereby enhancing MSCs' function and preventing osteoporosis. Our findings identify a nutrient-responsive signaling axis—nitrate-Sialin-pSTAT3<sup>S727</sup>—that promotes osteogenic differentiation via mitochondrial homeostasis, offering a potential therapeutic strategy for age-related osteoporosis.</p>

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Sialin-STAT3 axis regulates bone homeostasis in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月9日

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  • Xiaoyu Li,
  • Lei Hu,
  • Yifan Xu,
  • Xue Wang,
  • Zichen Cao,
  • Ou Jiang,
  • Jiawei Yao,
  • Meijing Liu,
  • Sihan Kong,
  • Jinsong Wang,
  • Xiaogang Wang,
  • Songlin Wang

摘要

Mitochondrial regulation in mesenchymal stem cells (MSCs) serves as a critical determinant of bone formation and skeletal homeostasis. While dietary nitrate and its transporter Sialin are implicated in systemic homeostasis, their specific roles in MSCs' function remain unclear. Here, we demonstrate that Sialin deficiency impairs MSCs' function and disrupts bone homeostasis. Gain- and loss-of-function studies reveal that Sialin localizes to the mitochondrial membrane and promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity. Mechanistically, Sialin recruits pSTAT3S727 to mitochondria, forming a functional complex that activates mitochondrial bioenergy and stabilizes bone remodeling. Notably, dietary nitrate restores Sialin expression in aged mice, thereby enhancing MSCs' function and preventing osteoporosis. Our findings identify a nutrient-responsive signaling axis—nitrate-Sialin-pSTAT3S727—that promotes osteogenic differentiation via mitochondrial homeostasis, offering a potential therapeutic strategy for age-related osteoporosis.