Expression of catalytically active matrix metalloproteinase‐1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin. Issue 4 (15th May 2013)

• Record Type: Journal Article
• Authors: Xia, Wei; Hammerberg, Craig; Li, Yong; He, Tianyuan; Quan, Taihao; Voorhees, John J.; Fisher, Gary J.
• Is Part Of: Aging cell. Volume 12:Issue 4(2013:Aug.)
• Page Start: 661
• Page End: 671
• Publication Date: 2013-05-15
• Subjects: aging -- extracellular matrix -- matrix metalloproteinase -- molecular biology of aging; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12089
• Languages: English
• ISSNs: 1474-9718

Abstract

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 siRNA‐mediated knockdown or MMP inhibitor MMI270. 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.