Snhg18 regulates Yap subcellular localization to maintain bone homeostasis

Jie Huang, Yuteng Weng, Yanhuizhi Feng, Di Wu, Yongliang Chen, Zeyuan Li, Xue Jiang, Haicheng Wang and Zuolin Wang ()
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Jie Huang: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Yuteng Weng: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Yanhuizhi Feng: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Di Wu: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Yongliang Chen: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Zeyuan Li: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Xue Jiang: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Haicheng Wang: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology
Zuolin Wang: Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62838-z

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