Matrix Metalloproteinase-1 Expression in Fibroblasts Accelerates Dermal Aging and Promotes Papilloma Development in Mouse Skin.



Quan, Taihao, Xia, Wei, He, Tianyuan, Calderone, Kenneth, Bou-Gharios, George, Voorhees, John J, Dlugosz, Andrzej A and Fisher, Gary J
(2023) Matrix Metalloproteinase-1 Expression in Fibroblasts Accelerates Dermal Aging and Promotes Papilloma Development in Mouse Skin. The Journal of investigative dermatology, 143 (9). S0022-202X(23)01827-4-S0022-202X(23)01827-4.

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Abstract

Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix (ECM) are hallmarks of aged human skin. These deleterious alterations are thought to critically mediate many of the prominent clinical attributes of aged skin including thinning, fragility, impaired wound healing, and propensity for carcinoma. Matrix metalloproteinase-1 (MMP1), initiates cleavage of collagen fibrils and is significantly increased in dermal fibroblasts in aged human skin. To investigate the role of elevated MMP1 in skin aging, we generated a conditional bitransgenic mouse (Col1a2;hMMP1) that expresses full-length, catalytically-active human MMP1 (hMMP1) in dermal fibroblasts. hMMP1 expression is activated by a tamoxifen-inducible Cre recombinase that is driven by the collagen1A2 (Col1a2) promoter and upstream enhancer. Tamoxifen induced hMMP1 expression and activity throughout the dermis in Col1a2 in hMMP1 mice. At six months of age, Col1a2;hMMP1 mice displayed loss and fragmentation of dermal collagen fibrils, which was accompanied by many of the features of aged human skin, such as contracted fibroblast morphology, reduced collagen production, increased expression of multiple endogenous MMPs and proinflammatory mediators. Interestingly, Col1a2;hMMP1 mice displayed substantially increased susceptibility to skin papilloma development. These data demonstrate that fibroblast expression of hMMP1 is a critical mediator of dermal aging and creates a dermal microenvironment that promotes keratinocyte tumor development.

Item Type: Article
Uncontrolled Keywords: Cells, Cultured, Fibroblasts, Skin, Animals, Humans, Mice, Papilloma, Collagen, Collagen Type I, Skin Aging, Aged, Matrix Metalloproteinase 1, Tumor Microenvironment
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User: Symplectic Admin
Date Deposited: 26 Apr 2023 09:34
Last Modified: 11 Mar 2024 02:30
DOI: 10.1016/j.jid.2023.02.028
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3169971