The effects of myostatin on adipogenic differentiation of human bone marrow-derived mesenchymal stem cells are mediated through cross-communication between Smad3 and Wnt/β-catenin signaling pathways
The effects of myostatin on adipogenic differentiation of human bone marrow-derived mesenchymal stem cells are mediated through cross-communication between Smad3 and Wnt/β-catenin signaling pathways
复制标题
DOI：
10.1074/jbc.m708968200
复制
发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Bhasin, Shalender
中科院分区：
文献类型：
--
作者：
Guo, Wen;Flanagan, John;Bhasin, Shalender
肌生长抑制素对成脂分化的影响知之甚少，其潜在机制尚不清楚。我们确定了人重组肌肉生长抑制素蛋白对骨髓来源的人间充质干细胞（hMSCs）和脂肪组织来源的前脂肪细胞的成脂作用。对于这两种祖细胞类型，在肌生长抑制素存在下的分化引起脂质积累的剂量依赖性减少和外源性脂肪酸掺入细胞脂质的减少。肌生长抑制素显著下调脂肪细胞标志物过氧化物酶体增殖物激活受体γ、C/EBP α、瘦素和aP 2的表达，但不下调C/EBP β的表达。过表达的过氧化物酶体增殖物激活受体γ，而不是C/EBP β，阻断肌肉生长抑制素对脂肪形成的抑制作用。肌肉生长抑制素诱导hMSCs中Smad 3的磷酸化;通过RNAi敲低Smad 3或通过Alk 5抑制剂抑制其上游激酶阻断了肌肉生长抑制素对hMSCs中脂肪形成的抑制作用，这意味着Smad 3激活在此事件中起重要作用。此外，肌肉生长抑制素增强β-连环蛋白的核转位和Smad 3-β-连环蛋白-TCF 4复合物的形成，以及hMSCs中许多Wnt/β-连环蛋白途径基因的表达改变。肌肉生长抑制素对脂肪生成的抑制作用通过β-连环蛋白的RNA干扰沉默而被阻断，并通过显性负性TCF 4的过表达而被减弱。结论是肌生长抑制素抑制人骨髓间充质干细胞和前脂肪细胞的脂肪形成。这些作用部分通过Smad 3的激活和TGF β/Smad信号与Wnt/β-连环蛋白/TCF 4通路的交叉通讯介导，导致PPAR γ的下调。
The effects of myostatin on adipogenic differentiation are poorly understood, and the underlying mechanisms are unknown. We determined the effects of human recombinant myostatin protein on adipogenesis of bone marrow-derived human mesenchymal stem cells (hMSCs) and adipose tissue-derived preadipocytes. For both progenitor cell types, differentiation in the presence of myostatin caused a dose-dependent reduction of lipid accumulation and diminished incorporation of exogenous fatty acid into cellular lipids. Myostatin significantly down-regulated the expression of adipocyte markers PPAR gamma, C/EBP alpha, leptin, and aP2, but not C/EBP beta. Overexpression of PPAR gamma, but not C/EBP beta,blocked the inhibitory effects of myostatin on adipogenesis. Myostatin induced phosphorylation of Smad3 in hMSCs; knockdown of Smad3 by RNAi or inhibition of its upstream kinase by an Alk5 inhibitor blocked the inhibitory effect of myostatin on adipogenesis in hMSCs, implying an important role of Smad3 activation in this event. Furthermore, myostatin enhanced nuclear translocation of beta-catenin and formation of the Smad3-beta-catenin-TCF4 complex, together with the altered expression of a number of Wnt/beta-catenin pathway genes in hMSCs. The inhibitory effects of myostatin on adipogenesis were blocked by RNAi silencing of beta-catenin and diminished by overexpression of dominant-negative TCF4. The conclusion is that myostatin inhibited adipogenesis in human bone marrow-derived mesenchymal stem cells and preadipocytes. These effects were mediated, in part, by activation of Smad3 and cross-communication of the TGF beta/Smad signal to Wnt/beta-catenin/TCF4 pathway, leading to down-regulation of PPAR gamma.