Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China.
Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China.
Cell Mol Life Sci. 2022 Aug 19;79(9):488. doi: 10.1007/s00018-022-04511-y.
An imbalance of human mesenchymal stem cells (hMSCs) adipogenic and osteogenic differentiation is crucial in the pathogenesis of osteoporosis, and elucidation of the underlying mechanism is urgently needed. APPL1, an adaptor protein of the adiponectin receptor, was recently shown to be closely related to bone mass. However, the role of APPL1 in the imbalance of hMSC differentiation in osteoporosis is unclear. Therefore, we aimed to explore the mechanisms by which APPL1 alters hMSCs adipogenic differentiation in osteoporosis. Here, we found that APPL1 expression was downregulated in elderly patients with osteoporosis and in mouse osteoporosis model. APPL1 negatively regulated hMSC adipogenic differentiation in vivo and in vitro. Mechanistically, by enhancing ubiquitination-mediated Myoferlin degradation, downregulated APPL1 expression increased the risk of lysosome dysfunction during hMSCs adipogenic differentiation. Lysosomal dysfunction inhibited autophagy flux by suppressing autophagosome degradation and promoted hMSC differentiation towards the adipocyte lineage. Our findings suggest that APPL1/Myoferlin downregulation promoted hMSCs adipogenic differentiation by inhibiting autophagy flux, further impairing the balance of hMSCs adipogenic and osteogenic differentiation in osteoporosis; the APPL1/ Myoferlin axis may be a promising diagnostic and therapeutic target for osteoporosis.
人骨髓间充质干细胞（hMSCs）成脂和成骨分化失衡在骨质疏松症的发病机制中至关重要，迫切需要阐明其潜在机制。脂联素受体的衔接蛋白 APPL1 最近被证明与骨量密切相关。然而，APPL1 在骨质疏松症 hMSC 分化失衡中的作用尚不清楚。因此，我们旨在探讨 APPL1 改变骨质疏松症中 hMSC 成脂分化的机制。在这里，我们发现 APPL1 在老年骨质疏松症患者和小鼠骨质疏松症模型中的表达下调。APPL1 在体内和体外均负调控 hMSC 成脂分化。机制上，通过增强泛素化介导的肌球蛋白重链（Myoferlin）降解，下调的 APPL1 表达增加了 hMSCs 成脂分化过程中溶酶体功能障碍的风险。溶酶体功能障碍通过抑制自噬体降解抑制自噬流，促进 hMSC 向脂肪细胞谱系分化。我们的研究结果表明，APPL1/Myoferlin 下调通过抑制自噬流促进 hMSCs 成脂分化，进一步破坏骨质疏松症中 hMSCs 成脂和成骨分化的平衡；APPL1/Myoferlin 轴可能是骨质疏松症有前途的诊断和治疗靶点。
