Snhg18 regulates Yap subcellular localization to maintain bone homeostasis.

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.