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<p>Osteoporosis treatments commonly mitigate bone loss but rarely restore lost bone mass. Yes-associated protein (Yap) nuclear translocation is crucial for the osteogenic differentiation of bone marrow stromal cells (BMSCs), but is disrupted by many factors under osteoporotic conditions. Long non-coding RNAs (lncRNAs) regulate BMSCs differentiation and Yap localization across diseases, exhibiting tissue- and cell-specific effects. However, their role in aberrant Yap signaling within BMSCs under osteoporosis remains unclear. Here, we identify small nucleolar RNA host gene 18 (<i>lnc-Snhg18</i>), a functionally conserved lncRNA enriched in the osteolineage of leptin receptor–positive (LepR⁺) cells within bone, as a key regulator promoting osteogenesis. Mechanistically, <i>lnc-Snhg18</i> directly binds Caveolin-1 (Cav1) and 14-3-3 eta protein (Ywhah), facilitating Cav1–Ywhah complex formation, thereby disrupting the Ywhah–Yap interaction and enabling Yap nuclear translocation. Knockout of <i>lnc-Snhg18</i> in LepR⁺ cells accelerates bone loss and traps Yap in the cytoplasm, while its delivery restores bone mass and Yap signaling in osteoporosis models. These findings identify <i>lnc-Snhg18</i> as a promising therapeutic target for osteoporosis and related disorders.</p>

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Snhg18 regulates Yap subcellular localization to maintain bone homeostasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月14日

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  • Jie Huang,
  • Yuteng Weng,
  • Yanhuizhi Feng,
  • Di Wu,
  • Yongliang Chen,
  • Zeyuan Li,
  • Xue Jiang,
  • Haicheng Wang,
  • Zuolin Wang

摘要

Osteoporosis treatments commonly mitigate bone loss but rarely restore lost bone mass. Yes-associated protein (Yap) nuclear translocation is crucial for the osteogenic differentiation of bone marrow stromal cells (BMSCs), but is disrupted by many factors under osteoporotic conditions. Long non-coding RNAs (lncRNAs) regulate BMSCs differentiation and Yap localization across diseases, exhibiting tissue- and cell-specific effects. However, their role in aberrant Yap signaling within BMSCs under osteoporosis remains unclear. Here, we identify small nucleolar RNA host gene 18 (lnc-Snhg18), a functionally conserved lncRNA enriched in the osteolineage of leptin receptor–positive (LepR⁺) cells within bone, as a key regulator promoting osteogenesis. Mechanistically, lnc-Snhg18 directly binds Caveolin-1 (Cav1) and 14-3-3 eta protein (Ywhah), facilitating Cav1–Ywhah complex formation, thereby disrupting the Ywhah–Yap interaction and enabling Yap nuclear translocation. Knockout of lnc-Snhg18 in LepR⁺ cells accelerates bone loss and traps Yap in the cytoplasm, while its delivery restores bone mass and Yap signaling in osteoporosis models. These findings identify lnc-Snhg18 as a promising therapeutic target for osteoporosis and related disorders.