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

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.

Age‐related dermal collagen changes during development, maturation and ageing – a morphometric and comparative study

“…To the paradigm in which several alterations in a cellular level provoke changes in the extracellular matrix (Chung et al 2001;Varani et al 2006) has been added, in the case of skin ageing, the model in which the extracellular matrix itself is able to exert influence over the cells and regulate several parameters related to ageing (Fisher et al 2008). Specifically, it has been demonstrated that the rests of fragmented collagen inhibit the synthesis of procollagen I and connective tissue growth factor (CTGF) by fibroblast, block their proliferation, induce a senescent fibroblastic morphology, alter the cell cytoskeleton, and stimulate the expression of MMP and synthesis of ROS (Varani et al 2001;Fisher et al 2009;Xia et al 2013).…”

Compound K inhibits MMP‐1 expression through suppression of c‐Src‐dependent ERK activation in TNF‐α‐stimulated dermal fibroblast

“…Among them, active MMP‐1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin. Thus, increased expression of MMP‐1 and reduced production of type I collagen by dermal fibroblasts are prominent features of aged human skin . Several reports showed that TNF‐ α induced MMP‐1 production by mitogen‐activated protein kinase (MAPK) and activator protein‐1 (AP‐1) pathways in RA synovial fibroblasts and by Raf‐1/MEK/ERK signalling pathways in HCS‐2/8 cells .…”

Ageing: collagenase‐mediated collagen fragmentation as a rejuvenation target

“…1). 18 In this less-stretched state, fibroblasts upregulate MMPs and downregulate the production of collagen. With repeated UV exposure, or the passage of time, accumulation of collagen fibril fragmentation shifts the balance in favour of MMP expression and collagen fibril fragmentation.…”