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Abstract
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.
Highlights
Human skin is composed of a dense collagen-rich connective tissue that provides structural and mechanical support (Uitto, 1986)
We previously reported that dermal fibroblasts in aged human skin expresses elevated matrix metalloproteinase 1 (MMP-1), which leads to collagen fibril fragmentation and disorganization, the hallmark of skin connective tissue aging (Fisher et al, 2008; Quan et al, 2013a)
We report that reduced fibroblast spreading and mechanical force activates transcription factor c-Jun/AP-1 leading to up-regulation of MMP-1 expression
Summary
Human skin is composed of a dense collagen-rich connective tissue that provides structural and mechanical support (Uitto, 1986). This collagenrich connective tissue is produced, organized, and maintained by dermal fibroblasts. Dermal connective tissue undergoes progressive alterations in part associated with age-related collagen fibril fragmentation and disorganization (Fisher et al, 2008, 2009). In aged dermis, collagen fibrils are fragmented, which reduces both fibroblast binding and mechanical stability These alterations impair fibroblast spreading, mechanical forces, and functions (Varani et al, 2004; Fisher et al, 2008; Quan et al, 2013b). While cell shape and mechanical forces are known to regulate many cellular functions, the molecular basis of their impact on dermal fibroblast function and skin connective tissue aging is not well understood
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