title: Cysteine-rich protein 61 (CCN1) domain-specific stimulation of matrix metalloproteinase-1 expression through αVβ3 integrin in human skin fibroblasts.
abstract: Human skin largely comprises collagenous extracellular matrix. The hallmark of skin aging is fragmentation of collagen fibrils. Matrix metalloproteinases (MMPs) are largely responsible for collagen degradation. MMP-1, principally derived from dermal fibroblasts, is the major protease capable of initiating degradation of native fibrillar collagens. Presently, we report that CCN1, a secreted and extracellular matrix-associated protein, is elevated in aged human skin dermal fibroblasts in vivo and stimulates MMP-1 expression through functional interaction with αVβ3 integrin in human dermal fibroblasts. CCN1 contains four conserved structural domains. Our results indicate that the three N-terminal domains (IGFBP, VWC, and TSP1), but not the C-terminal CT domain, are required for CCN1 to stimulate MMP-1 expression. This stimulation is dependent on interaction between the active structural domains and αVβ3 integrin. The interaction of VWC domain with integrin αVβ3 is necessary and requires functional cooperation with adjacent IGFBP and TSP1 domains to stimulate MMP-1 expression. Finally, induction of MMP-1 expression in dermal fibroblasts by CCN1 N-terminal domains resulted in fragmentation of type I collagen fibrils in a three-dimensional collagen lattice model. These data suggest that domain-specific interactions of CCN1 with αVβ3 integrin contribute to human skin aging by stimulating MMP-1-mediated collagen fibril fragmentation.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Qin
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
authors.forename: Taihao
authors.initials: T
authors.lastname: Quan
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D020405:Dermis / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: C501848:CCN1 protein, human; D024042:Collagen Type I; D055515:Cysteine-Rich Protein 61; D039302:Integrin alphaVbeta3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1