Abstract
Human skin is a primary target of oxidative stress from reactive oxygen species (ROS) generated from both extrinsic and intrinsic sources. Oxidative stress inhibits the production of collagen, the most abundant protein in skin, and thus contributes to connective tissue aging. Here we report that cysteine-rich protein 61 (CCN1), a negative regulator of collagen production, is markedly induced by ROS and mediates loss of type I collagen in human dermal fibroblasts. Conversely, antioxidant N-acetyl-L-cysteine significantly reduced CCN1 expression and prevented ROS-induced loss of type I collagen in both human dermal fibroblasts and human skin in vivo. ROS increased c-Jun, a critical member of transcription factor AP-1 complex, and increased c-Jun binding to the AP-1 site of the CCN1 promoter. Functional blocking of c-Jun significantly reduced CCN1 promoter and gene expression and thus prevented ROS-induced loss of type I collagen. Targeting the c-Jun/CCN1 axis may provide clinical benefit for connective tissue aging in human skin.
Highlights
Oxidative stress is an important pathogenic factor involved in human aging [1, 2]
We previously reported that cysteine-rich protein 61 (CCN1), a secreted and extracellular matrixassociated protein, is predominantly expressed in human skin dermal fibroblasts, and is substantially elevated in the dermis of naturally aged [14, 15], photoaged [14, 16] and acutely ultraviolet irradiation (UV)-irradiated human skin in vivo [17, 18]
We first investigated the response of human dermal fibroblasts to low levels of the naturally occurring pro-oxidant hydrogen peroxide
Summary
Human skin is exposed to reactive oxygen species (ROS) generated from both environmental sources like ultraviolet irradiation (UV) (photoaging) [3, 4] and endogenous oxidative metabolism (natural aging) [5]. These oxidative stresses impair the synthesis of collagen, the major structural protein in skin, and PLOS ONE | DOI:10.1371/journal.pone.0115402. A characteristic feature of aged human skin is thinning of the dermis and diminished tensile strength caused by loss of dermal connective tissue collagen [7,8,9]. Loss of collagen has deleterious effects on skin structural integrity and function, and contributes to common aged-related skin problems such as impaired wound healing and increased risk for skin cancer [10,11,12,13]
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