Decreased Collagen Production in Chronologically Aged Skin

Varani, James; Dame, Michael K.; Rittié, Laure; Fligiel, Suzanne E. G.; Kang, Sewon; Fisher, Gary J.; Voorhees, John J.

doi:10.2353/ajpath.2006.051302

Cited by 688 publications

(336 citation statements)

References 38 publications

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“…In aged skin, fibroblasts adjacent to fragmented collagen are less stretched, and by inference have lower mechanical tension. 6,85 Our results in collagen lattices demonstrate that collagen fragmentation causes loss of stretch, which results in increased levels of oxidants. Mechanism(s) by which loss of stretch (or mechanical tension) results in increased oxidative stress in fibroblasts is currently unknown.…”

Section: Discussionmentioning

confidence: 85%

Collagen Fragmentation Promotes Oxidative Stress and Elevates Matrix Metalloproteinase-1 in Fibroblasts in Aged Human Skin

Fisher

Quan

Purohit

et al. 2009

The American Journal of Pathology

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Aged human skin is fragile because of fragmentation and loss of type I collagen fibrils, which confer strength and resiliency. We report here that dermal fibroblasts express increased levels of collagen-degrading matrix metalloproteinases-1 (MMP-1) in aged (>80 years old) compared with young (21 to 30 years old) human skin in vivo. Transcription factor AP-1 and ␣2␤1 integrin, which are key regulators of MMP-1 expression, are also elevated in fibroblasts in aged human skin in vivo. MMP-1 treatment of young skin in organ culture causes fragmentation of collagen fibrils and reduces fibroblast stretch, consistent with reduced mechanical tension , as observed in aged human skin. Limited fragmentation of three-dimensional collagen lattices with exogenous MMP-1 also reduces fibroblast stretch and mechanical tension. Furthermore, fibroblasts cultured in fragmented collagen lattices express elevated levels of MMP-1, AP-1, and ␣2␤1 integrin. Importantly, culture in fragmented collagen raises intracellular oxidant levels and treatment with antioxidant MitoQ 10 significantly reduces MMP-1 expression. These data identify positive feedback regulation that couples age-dependent MMP-1-catalyzed collagen fragmentation and oxidative stress. We propose that this self perpetuating cycle promotes human skin aging. These data extend the current understanding of the oxidative theory of aging beyond a cellular-centric view to include extracellular matrix and the critical role that connective tissue microenvironment plays in the biology of aging. Skin connective tissue (dermis) provides structural support for the skin's vasculature, appendages, and epidermis, which are vital to the function of skin. Structural integrity and function of the dermis are primarily dependent on its extracellular matrix, which is primarily composed of type I collagen fibrils. Type I collagen is the most abundant structural protein in skin, 1 and fragmented collagen fibrils are prominent, characteristic features of aged human skin in vivo.2-4 This fragmentation seriously impairs both the mechanical properties of skin, and the functions of cells that reside within the dermis. Clinically, this impairment manifests as delayed wound healing, reduced vascularization, propensity to bruise, and thin skin. Failure of normal functional interactions among dermal cells and their extracellular matrix microenvironment underlie these age-dependent phenotypic alterations. 6Damage to the collagenous extracellular matrix of the dermis can be observed at both the histological and ultrastructural level. 5,[7][8][9] In young dermis, intact, tightly packed, well-organized, long collagen fibrils are abundant. In contrast, in aged dermis, collagen fibrils are fragmented, disorganized, and sparse, resulting in the appearance of amorphous open space. Quantitative biochemical analysis reveals that the amount of fragmented collagen is 4.3-fold greater in aged (Ͼ80 years old) compared with young (21 to 30 years old) human dermis in vivo.

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Section: Discussionmentioning

confidence: 85%

Collagen Fragmentation Promotes Oxidative Stress and Elevates Matrix Metalloproteinase-1 in Fibroblasts in Aged Human Skin

Fisher

Quan

Purohit

et al. 2009

The American Journal of Pathology

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386

412

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“…We previously reported that fibroblasts in aged human skin display a contracted, rounded morphology with 50% less surface area (Varani et al ., 2006). Therefore, we determined whether reduced fibroblast size in aged skin is associated with reduced TβRII gene expression.…”

Section: Resultsmentioning

confidence: 99%

“…Fibroblasts are unable to attach to the fragmented ECM and therefore cannot exert traction forces needed to spread, and appear contracted. We and others have previously reported that many TGF‐β‐regulated genes involved in ECM production are reduced in aged human skin (Varani et al ., 2006; Quan et al ., 2010). Importantly, TβRII expression is also reduced in aged skin (Quan et al ., 2006; Quan & Fisher, 2015), suggesting that impaired TGF‐β signaling may be a key mediator of reduced ECM production.…”

Section: Discussionmentioning

confidence: 99%

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Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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SummaryThe structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.

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“…They observed that mesenchymal stem cells could significantly increase wound healing by activating matrix metalloproteinase 9 and vascular endothelial growth factor. The literature suggests the use of these cells in various therapeutic interventions, such as treatment of ulcers due to surgery or burns, chronic ulcers, treatment resistance in diabetic ulcers, and shallow or deep wrinkles of the skin (18,19).…”

Section: Function Of Fibroblastsmentioning

confidence: 99%

Dermal Fibroblast Cells: Biology and Function in Skin Regeneration

et al. 2017

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Fibroblasts are mesenchymal cells, which play an important role in epithelial-mesenchymal reactions. These cells also play a key role in epidermal proliferation and differentiation and cellular matrix formation through secretion of different growth factors and cytokines. Cell therapy is a new treatment for skin diseases. In fact, conditions, such as burns, diabetic wounds, scars, and aging skin, have been treated with these cells. In cell therapy, samples obtained from the patient's skin are isolated and cultured; then, the cells are injected into damaged tissues. In recent years, several clinical trials have been conducted in this area, and numerous studies have been published. In this review, we aimed to investigate the biology and function of these cells in the treatment of skin diseases.

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Decreased Collagen Production in Chronologically Aged Skin

Cited by 688 publications

References 38 publications

Collagen Fragmentation Promotes Oxidative Stress and Elevates Matrix Metalloproteinase-1 in Fibroblasts in Aged Human Skin

Collagen Fragmentation Promotes Oxidative Stress and Elevates Matrix Metalloproteinase-1 in Fibroblasts in Aged Human Skin

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

Dermal Fibroblast Cells: Biology and Function in Skin Regeneration

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