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

Aging Cell. 2014 Dec;13(6):1028-37. doi: 10.1111/acel.12265. Epub 2014 Sep 9.

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.

Keywords: MMP-1; aging; c-Jun/AP-1; extracellular matrix microenvironment; fibroblast; mechanical force.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Biomechanical Phenomena
  • Cell Movement / physiology
  • Cells, Cultured
  • Collagen / genetics
  • Collagen / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Matrix Metalloproteinase 1 / biosynthesis*
  • Matrix Metalloproteinase 1 / genetics
  • Signal Transduction
  • Skin / cytology
  • Skin / enzymology
  • Skin / metabolism
  • Transcription Factor AP-1 / metabolism*

Substances

  • Transcription Factor AP-1
  • Collagen
  • JNK Mitogen-Activated Protein Kinases
  • MMP1 protein, human
  • Matrix Metalloproteinase 1