Expression of catalytically active matrix metalloproteinase‐1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin

Aging Cell

Wei Xia¹  Craig Hammerberg¹  Yong Li¹  Tianyuan He¹  Taihao Quan¹  John J. Voorhees¹ 

[1] Department of Dermatology, University of Michigan, 1301 E Catherine, R6447 Med Sci I, Ann Arbor, MI 48109-5609, USA

关键词: aging;    extracellular matrix;    matrix metalloproteinase;    molecular biology of aging;   

DOI  :  10.1111/acel.12089

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
© 2013 John Wiley & Sons Ltd and the Anatomical Society