Open AccessExpression of catalytically active matrix metalloproteinase‐1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin
Author(s) -
Xia Wei,
Hammerberg Craig,
Li Yong,
He Tianyuan,
Quan Taihao,
Voorhees John J.,
Fisher Gary J.
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12089
Subject(s) - fibroblast , matrix metalloproteinase , microbiology and biotechnology , biology , collagen, type i, alpha 1 , extracellular matrix , human skin , type i collagen , fragmentation (computing) , organ culture , collagen vi , gene knockdown , fibril , cell culture , in vitro , endocrinology , biochemistry , genetics , ecology
Summary Increased expression of matrix metalloproteinase‐1 ( MMP ‐1) and reduced production of type I collagen by dermal fibroblasts are prominent features of aged human skin. We have proposed that MMP ‐1‐mediated collagen fibril fragmentation is a key driver of age‐related decline of skin function. To investigate this hypothesis, we constructed, characterized, and expressed constitutively active MMP ‐1 mutant ( MMP ‐1 V94G) in adult human skin in organ culture and fibroblasts in three‐dimensional collagen lattice cultures. Expression of MMP ‐1 V94G in young skin in organ culture caused fragmentation and ultrastructural alterations of collagen fibrils similar to those observed in aged human skin in vivo . Expression of MMP ‐1 V94G in dermal fibroblasts cultured in three‐dimensional collagen lattices caused substantial collagen fragmentation, which was markedly reduced by MMP ‐1 si RNA ‐mediated knockdown or MMP inhibitor MMI 270. Importantly, fibroblasts cultured in MMP ‐1 V94G‐fragmented collagen lattices displayed many alterations observed in fibroblasts in aged human skin, including reduced cytoplasmic area, disassembled actin cytoskeleton, impaired TGF ‐β pathway, and reduced collagen production. These results support the concept that MMP ‐1‐mediated fragmentation of dermal collagen fibrils alters the morphology and function of dermal fibroblasts and provide a foundation for understanding specific mechanisms that link collagen fibril fragmentation to age‐related decline of fibroblast function.