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Abstract：
An imbalance of human mesenchymal stem cells (MSCs) adipogenic and osteogenic differentiation plays an important role in the pathogenesis of osteoporosis. Our previous study verified that Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)/myoferlin deficiency promotes adipogenic differentiation of MSCs by blocking autophagic flux in osteoporosis. However, the function of APPL1 in the osteogenic differentiation of MSCs remains unclear. This study aimed to investigate the role of APPL1 in the osteogenic differentiation of MSCs in osteoporosis and the underlying regulatory mechanism. In this study, we demonstrated the downregulation of APPL1 expression in patients with osteoporosis and osteoporosis mice. The severity of clinical osteoporosis was negatively correlated with the expression of APPL1 in bone marrow MSCs. We found that APPL1 positively regulates the osteogenic differentiation of MSCs in vitro and in vivo. Moreover, RNA sequencing showed that the expression of MGP, an osteocalcin/matrix Gla family member, was significantly upregulated after APPL1 knockdown. Mechanistically, our study showed that reduced APPL1 impaired the osteogenic differentiation of mesenchymal stem cells by facilitating Matrix Gla protein expression to disrupt the BMP2 pathway in osteoporosis. We also evaluated the significance of APPL1 in promoting osteogenesis in a mouse model of osteoporosis. These results suggest that APPL1 may be an important target for the diagnosis and treatment of osteoporosis.
摘要：
人骨髓间充质干细胞（MSCs）成脂和成骨分化失衡在骨质疏松症的发病机制中起着重要作用。我们之前的研究证实了衔接子蛋白，磷酸酪氨酸与PH结构域和亮氨酸拉链1（APPL1）相互作用/肌铁蛋白缺乏通过阻断骨质疏松中的自噬通量促进MSCs的成脂分化。然而,APPL1在MSCs成骨分化中的作用尚不清楚。本研究旨在探讨APPL1在骨质疏松骨髓间充质干细胞成骨分化中的作用及其调控机制。在这项研究中,我们证明了APPL1在骨质疏松症患者和骨质疏松症小鼠中的表达下调。临床骨质疏松的严重程度与骨髓间充质干细胞APPL1的表达呈负相关。我们发现APPL1在体外和体内正向调节MSCs的成骨分化。此外，RNA测序显示MGP的表达,骨钙蛋白/基质Gla家族成员，APPL1敲低后显著上调。机械上,我们的研究表明，减少的APPL1通过促进基质Gla蛋白表达来破坏骨质疏松中的BMP2通路，从而损害间充质干细胞的成骨分化。我们还评估了APPL1在骨质疏松症小鼠模型中促进成骨的意义。这些结果表明APPL1可能是诊断和治疗骨质疏松症的重要靶点。
