Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Shanghai, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
J Cell Mol Med. 2018 Oct;22(10):5097-5108. doi: 10.1111/jcmm.13798. Epub 2018 Jul 25.
Accelerated marrow adipogenesis has been associated with ageing and osteoporosis and is thought to be because of an imbalance between adipogenic and osteogenic differentiation of mesenchymal stem cell (MSCs). We have previously found that lysyl oxidase (Lox) inhibition disrupts BMP4-induced adipocytic lineage commitment and differentiation of MSCs. In this study, we found that lox inhibition dramatically up-regulates BMP4-induced expression of CCAAT/enhancer binding protein (C/EBP) homologous protein 10 (CHOP-10), which then promotes BMP4-induced osteogenesis of MSCs both in vitro and in vivo. Specifically, Lox inhibition or CHOP-10 up-regulation activated Wnt/β-catenin signalling to enhance BMP4-induced osteogenesis, with pro-adipogenic p38 MAPK and Smad signalling suppressed. Together, we demonstrate that Lox/CHOP-10 crosstalk regulates BMP4-induced osteogenic and adipogenic fate determination of MSCs, presenting a promising therapeutic target for osteoporosis and other bone diseases.
加速骨髓脂肪生成与衰老和骨质疏松有关，据认为这是由于间充质干细胞 (MSCs) 的脂肪生成和成骨分化之间失衡所致。我们之前发现赖氨酰氧化酶 (Lox) 抑制会破坏 BMP4 诱导的脂肪细胞谱系承诺和 MSC 的分化。在这项研究中，我们发现 Lox 抑制显着上调 BMP4 诱导的 CCAAT/增强子结合蛋白 (C/EBP) 同源蛋白 10 (CHOP-10) 的表达，从而促进 MSC 的 BMP4 诱导成骨作用在体外和体内。具体而言，Lox 抑制或 CHOP-10 的上调激活了 Wnt/β-catenin 信号通路，以增强 BMP4 诱导的成骨作用，同时抑制了促脂肪生成的 p38 MAPK 和 Smad 信号通路。总之，我们证明 Lox/CHOP-10 串扰调节 BMP4 诱导的 MSC 成骨和成脂命运决定，为骨质疏松症和其他骨骼疾病提供了有前途的治疗靶点。
