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

Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix 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 a propensity for carcinoma. Matrix metalloproteinase-1 (MMP1) initiates the 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 (type I collagen alpha chain 2; human MMP1 [Col1a2;hMMP1]) that expresses full-length, catalytically active hMMP1 in dermal fibroblasts. hMMP1 expression is activated by a tamoxifen-inducible Cre recombinase that is driven by the Col1a2 promoter and upstream enhancer. Tamoxifen induced hMMP1 expression and activity throughout the dermis Col1a2:hMMP1 mice. At 6 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.

Alterations in extracellular matrix composition during aging and photoaging of the skin.

Human skin is composed of the cell-rich epidermis, the extracellular matrix (ECM) rich dermis, and the hypodermis. Within the dermis, a dense network of ECM proteins provides structural support to the skin and regulates a wide variety of signaling pathways which govern cell proliferation and other critical processes. Both intrinsic aging, which occurs steadily over time, and extrinsic aging (photoaging), which occurs as a result of external insults such as solar radiation, cause alterations to the dermal ECM. In this study, we utilized both quantitative and global proteomics, alongside single harmonic generation (SHG) and two-photon autofluorescence (TPAF) imaging, to assess changes in dermal composition during intrinsic and extrinsic aging. We find that both intrinsic and extrinsic aging result in significant decreases in ECM-supporting proteoglycans and structural ECM integrity, evidenced by decreasing collagen abundance and increasing fibril fragmentation. Intrinsic aging also produces changes distinct from those produced by photoaging, including reductions in elastic fiber and crosslinking enzyme abundance. In contrast, photoaging is primarily defined by increases in elastic fiber-associated protein and pro-inflammatory proteases. Changes associated with photoaging are evident even in young (mid 20s) sun-exposed forearm skin, indicating that proteomic evidence of photoaging is present decades prior to clinical signs of photoaging. GO term enrichment revealed that both intrinsic aging and photoaging share common features of chronic inflammation. The proteomic data has been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD015982.