MMP-2 expression by fibroblasts is suppressed by the myofibroblast phenotype

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• 作者：Eric W. Howard^a ; ^{eric-howard@ouhsc.edu} ; Beverly J. Crider^a ; Dawn L. Updike^a ; Elizabeth C. Bullen^a ; Eileen E. Parks^a ; Carol J. Haaksma^a ; David M. Sherry^a ; ^b ; ^c ; James J. Tomasek^a
• 关键词：DMEM ; Dulbecco's Modified Eagle's Medium ; ECM ; extracellular matrix ; ET-1 ; endothelin ; GAPDH ; glyceraldehyde 3-phosphate dehydrogenase ; GPCR ; G-protein-coupled receptor ; IGF-I ; insulin-like growth factor-I ; Lat B ; Latrunculin B ; MMP ; matrix metalloprotein
• 刊名：Experimental Cell Research
• 出版年：2012
• 期刊代码：292_00144827
• 类别：med
• 出版时间：1 August, 2012
• 卷：318
• 期：13
• 页码：1542-1553
• 文件大小：1221 K

摘要

During wound healing, fibroblasts transition from quiescence to a migratory state, then to a contractile myofibroblast state associated with wound closure. We found that the myofibroblast phenotype, characterized by the expression of high levels of contractile proteins, suppresses the expression of the pro-migratory gene, MMP-2. Fibroblasts cultured in a 3-D collagen lattice and allowed to develop tension showed increased contractile protein expression and decreased MMP-2 levels in comparison to a stress-released lattice. In 2-D cultures, factors that promote fibroblast contractility, including serum or TGF-尾, down-regulated MMP-2. Pharmacologically inducing F-actin disassembly or reduced contractility increased MMP-2 expression, while conditions that promote F-actin assembly suppressed MMP-2 expression. In all cases, changes in MMP-2 levels were inversely related to changes in the contractile marker, smooth muscle 伪-actin. To determine if the mechanisms involved in contractile protein gene expression play a direct role in MMP-2 regulation, we used RNAi-mediated knock-down of the myocardin-like factors, MRTF-A and MRTF-B, which induced the down-regulation of contractile protein genes by fibroblasts under both serum-containing and serum-free conditions. In the presence of serum or TGF-尾, MRTF-A/B knock-down resulted in the up-regulation of MMP-2; serum-free conditions prevented this increased expression. Together, these results indicate that, while MMP-2 expression is suppressed by F-actin formation, its up-regulation is not simply a consequence of contractile protein down-regulation.