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.
Level 5 - mechanism / opinion, no new human data
In vitro bench research examining cellular and molecular mechanisms in cultured human fibroblasts
PubMed 25201474 · doi:10.1111/acel.12265
What was done
Investigators examined the relationship between cell spreading, mechanical force, matrix metalloproteinase-1 (MMP-1) expression, and collagen fragmentation in cultured human dermal fibroblasts. Fibroblast spreading was mechanically restricted using cytoskeletal disruption or collagen micropatterned substrates. Cellular mechanical forces were measured using atomic force microscopy, and collagen matrix reorganization was evaluated in three-dimensional collagen lattices. The transcriptional pathway was assessed by measuring c-Jun expression, testing c-Jun binding to the MMP-1 AP-1 promoter, blocking activity with a dominant-negative c-Jun mutant, and evaluating the effects of restoring cell spreading.
What was found
No quantitative values, effect sizes, or p-values were provided in the abstract. Disruption of fibroblast spreading reduced cellular mechanical force and significantly induced MMP-1 expression, which led to collagen fibril fragmentation and disorganization in three-dimensional lattices. Restricting cell size on collagen micropatterns also induced MMP-1. Reduced spreading/force upregulated transcription factor c-Jun and increased its binding to the canonical AP-1 promoter site on MMP-1. Blocking c-Jun with a dominant-negative mutant significantly decreased MMP-1 induction, while restoring cellular spreading and mechanical force lowered c-Jun and MMP-1 levels and eliminated collagen fragmentation.
Why it matters
This study defines a mechanobiological mechanism showing that loss of physical spreading and mechanical tension directly triggers MMP-1-mediated collagen breakdown via c-Jun/AP-1 signaling. It helps explain how physical structural changes in aging skin can self-propagate extracellular matrix degradation.
Limits
Findings are limited to in vitro 2D and 3D cell culture models and lack direct in vivo human skin validation. The abstract reports no sample size, donor numbers, donor age/sex characteristics, or quantitative measurements.
Cited by
- supports Matrix metalloproteinases (MMPs) degrade collagen and increase significantly with aging.