INSERM, U626, Faculté de Médecine, Université de la Méditérranée, 27 Boulevard Jean Moulin, Marseilles 13385 Cedex 5, France.
J Biol Chem. 2010 Feb 26;285(9):6508-14. doi: 10.1074/jbc.M109.078444. Epub 2010 Jan 7.
Matrix metalloproteinase activity is essential for proper extracellular matrix remodeling that takes place during adipose tissue formation. Four tissue inhibitors of matrix metalloproteinases (TIMPs) regulate their activity. However, the role of TIMPs in adipocyte differentiation is poorly understood. We found that the expression of all TIMPs was modified during adipocyte differentiation, but that of TIMP-3 was distinguished by its extreme down-regulation. TIMP-3 expression was closely linked to the differentiation process. Indeed, it remained low during the adipocyte differentiation but increased when cell differentiation was prevented. We identified the transcription factor Sp1 as being responsible for the regulation of TIMP-3 expression during adipocyte differentiation. Overexpression of TIMP-3 reduced adipocyte differentiation, underlining its active role in this process. TIMP-3 overexpression decreased the expression of the early and obligate key inductors of adipogenesis Krüppel-like factor 4 (Klf4), early growth response 2 (Egr2/Krox20), and CAAT/enhancer-binding protein beta (C/EBPbeta). Our results indicate that during preadipocyte differentiation, the Sp1-dependent decrease in TIMP-3 expression is required for the successful implementation of the adipocyte differentiation program.
基质金属蛋白酶活性对于脂肪组织形成过程中发生的适当细胞外基质重塑是必不可少的。四种基质金属蛋白酶组织抑制剂 (TIMP) 调节其活性。然而，TIMP 在脂肪细胞分化中的作用知之甚少。我们发现所有 TIMP 的表达在脂肪细胞分化过程中都发生了改变，但 TIMP-3 的表达却因其极度下调而与众不同。TIMP-3 的表达与分化过程密切相关。事实上，它在脂肪细胞分化过程中一直保持低水平，但当细胞分化被阻止时，它会增加。我们确定转录因子 Sp1 负责调节脂肪细胞分化过程中的 TIMP-3 表达。TIMP-3 的过表达减少了脂肪细胞的分化，突出了它在这个过程中的积极作用。TIMP-3 的过表达降低了早期和必需的脂肪生成关键诱导因子 Krüppel 样因子 4 (Klf4)、早期生长反应 2 (Egr2/Krox20) 和 CAAT/增强子结合蛋白 β (C/EBPβ) 的表达。我们的结果表明，在脂肪前体细胞分化过程中，Sp1 依赖性 TIMP-3 表达的降低是成功实施脂肪细胞分化程序所必需的。
