Age-associated reduction of cellular spreading/mechanical force up-regulates matrix metalloproteinase-1 expression and collagen fibril fragmentation via c-Jun/AP-1 in human dermal fibroblasts.
Age-associated reduction of cellular spreading/mechanical force up-regulates matrix metalloproteinase-1 expression and collagen fibril fragmentation via c-Jun/AP-1 in human dermal fibroblasts.
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DOI：
10.1111/acel.12265
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发表时间：
2014-12
期刊：
影响因子：
7.8
通讯作者：
Quan T
中科院分区：
文献类型：
--
作者：
Qin Z;Voorhees JJ;Fisher GJ;Quan T
人体皮肤的真皮隔室主要由致密的富含胶原蛋白的原纤维组成，提供结构和机械支撑。皮肤真皮成纤维细胞是主要的胶原蛋白生成细胞，与胶原纤维相互作用以维持细胞扩散和机械力以实现功能。老化人类皮肤的一个特征是胶原纤维断裂，这是由基质金属蛋白酶 1 (MMP-1) 引发的。破碎会损害成纤维细胞的附着，从而减少扩散。在这里，我们研究了成纤维细胞扩散、机械力、MMP-1 表达和胶原纤维断裂之间的关系。通过原子力显微镜测定，由于细胞骨架破坏而导致的成纤维细胞扩散减少与细胞机械力减少有关。这些减少显着诱导 MMP-1 表达，从而导致三维胶原蛋白晶格中的胶原原纤维断裂和解体。通过在涂有胶原微图案的载玻片上培养来限制成纤维细胞大小也显着诱导 MMP-1 表达。减少的扩散/机械力诱导转录因子 c-Jun 及其与 MMP-1 近端启动子中典型 AP-1 结合位点的结合。用显性失活突变体 c-Jun 阻断 c-Jun 功能，可显着降低因铺展/机械力降低而引起的 MMP-1 表达诱导。此外，成纤维细胞扩散/机械力的恢复导致 c-Jun 和 MMP-1 水平下降，并消除胶原纤维断裂和解体。这些数据揭示了一种新机制，成纤维细胞形状/机械力的改变可调节 MMP-1 的 c-Jun/AP-1 依赖性表达以及随之而来的胶原纤维断裂。这种机制为了解人类皮肤中与年龄相关的胶原蛋白断裂的细胞和分子基础奠定了基础。
The dermal compartment of human skin is largely composed of dense collagen-rich fibrils, which provide structural and mechanical support. Skin dermal fibroblasts, the major collagen-producing cells, are interact with collagen fibrils to maintain cell spreading and mechanical force for function. A characteristic feature of aged human skin is fragmentation of collagen fibrils, which is initiated by matrix metalloproteinase 1 (MMP-1). Fragmentation impairs fibroblast attachment and thereby reduces spreading. Here, we investigated the relationship among fibroblast spreading, mechanical force, MMP-1 expression, and collagen fibril fragmentation. Reduced fibroblast spreading due to cytoskeletal disruption was associated with reduced cellular mechanical force, as determined by atomic force microscopy. These reductions substantially induced MMP-1 expression, which led to collagen fibril fragmentation and disorganization in three-dimensional collagen lattices. Constraining fibroblast size by culturing on slides coated with collagen micropatterns also significantly induced MMP-1 expression. Reduced spreading/mechanical force induced transcription factor c-Jun and its binding to a canonical AP-1 binding site in the MMP-1 proximal promoter. Blocking c-Jun function with dominant negative mutant c-Jun significantly reduced induction of MMP-1 expression in response to reduced spreading/mechanical force. Furthermore, restoration of fibroblast spreading/mechanical force led to decline of c-Jun and MMP-1 levels and eliminated collagen fibril fragmentation and disorganization. These data reveal a novel mechanism by which alteration of fibroblast shape/mechanical force regulates c-Jun/AP-1-dependent expression of MMP-1 and consequent collagen fibril fragmentation. This mechanism provides a foundation for understanding the cellular and molecular basis of age-related collagen fragmentation in human skin.
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影响因子：
15.9
作者：
Fisher, GJ;Datta, S;Voorhees, JJ
通讯作者：
Voorhees, JJ
DOI：
10.1038/jid.2012.364
发表时间：
2013-03
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Quan T;Wang F;Shao Y;Rittié L;Xia W;Orringer JS;Voorhees JJ;Fisher GJ
通讯作者：
Fisher GJ
DOI：
10.1126/science.1176009
发表时间：
2009-11-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hynes RO
通讯作者：
Hynes RO
DOI：
10.1083/jcb.201102147
发表时间：
2012-02-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lu P;Weaver VM;Werb Z
通讯作者：
Werb Z
影响因子：
--
作者：
Fisher, Gary J.;Varani, James;Voorhees, John J.
通讯作者：
Voorhees, John J.