Fan Shuai, Li Jinteng, Zheng Guan, Ma Ziyue, Peng Xiaoshuai, Xie Zhongyu, Liu Wenjie, Yu Wenhui, Lin Jiajie, Su Zepeng, Xu Peitao, Wang Peng, Wu Yanfeng, Shen Huiyong, Ye Guiwen
Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, P. R. China.
Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, P. R. China.
Adv Sci (Weinh). 2025 Jan;12(2):e2404107. doi: 10.1002/advs.202404107. Epub 2024 Nov 18.
Osteogenic differentiation of mesenchymal stem cells (MSCs) plays a pivotal role in the pathogenesis and treatment of bone-related conditions such as osteoporosis and bone regeneration. While the WW domain-containing coiled-coil adaptor (WAC) protein is primarily associated with transcriptional regulation and autophagy, its involvement in MSC osteogenesis remains unclear. Here, the data reveal that the levels of WAC are diminished in both osteoporosis patients and osteoporosis mouse models. It plays a pivotal function in facilitating MSC osteogenesis and enhancing new bone formation both in vitro and in vivo. Mechanistically, WAC promotes MSC osteogenesis by protecting PINK1, a crucial initiator of mitophagy, from ubiquitination-dependent degradation thereby activating mitophagy. Interestingly, WAC interacts with the TM domains of PINK1 and prevents the K137 site from ubiquitination modification. The study elucidates the mechanism by which WAC modulates MSC osteogenesis, binds to PINK1 to protect it from ubiquitination, and identifies potential therapeutic targets for osteoporosis and bone defect repair.
间充质干细胞（MSC）的成骨分化在骨质疏松症和骨再生等骨相关疾病的发病机制和治疗中起着关键作用。虽然含WW结构域的卷曲螺旋衔接蛋白（WAC）主要与转录调控和自噬相关，但其在MSC成骨中的作用仍不清楚。在此，数据显示骨质疏松症患者和骨质疏松症小鼠模型中WAC水平均降低。它在促进MSC成骨和增强体内外新骨形成方面发挥关键作用。机制上，WAC通过保护线粒体自噬的关键启动子PINK1免受泛素化依赖性降解从而激活线粒体自噬，来促进MSC成骨。有趣的是，WAC与PINK1的跨膜结构域相互作用，并防止K137位点发生泛素化修饰。该研究阐明了WAC调节MSC成骨、与PINK1结合以保护其免受泛素化的机制，并确定了骨质疏松症和骨缺损修复的潜在治疗靶点。
