Ultraviolet Irradiation Induces CYR61/CCN1, a Mediator of Collagen Homeostasis, through Activation of Transcription Factor AP-1 in Human Skin Fibroblasts

Abstract

UV irradiation from the sun elevates the production of collagen-degrading matrix metalloproteinases (MMPs) and reduces the production of new collagen. This imbalance of collagen homeostasis impairs the structure and function of the dermal collagenous extracellular matrix (ECM), thereby promoting premature skin aging (photoaging). We report here that aberrant dermal collagen homeostasis in UV-irradiated human skin is mediated in part by a CCN-family member, cysteine-rich protein-61 (CYR61/CCN1). CYR61 is significantly elevated in acutely UV-irradiated human skin in vivo, and UV-irradiated human skin fibroblasts. Knockdown of CYR61 significantly attenuates UV irradiation-induced inhibition of type-I procollagen and upregulation of MMP-1. Determination of CYR61 mRNA and protein indicates that the primary mechanism of CYR61 induction by UV irradiation is transcriptional. Analysis of CYR61 proximal promoter showed that a sequence conforming to the consensus binding site for transcription factor activator protein-1 (AP-1) is required for promoter activity. UV irradiation increased the binding of AP-1-family members c-Jun and c-Fos to this AP-1 site. Furthermore, functional blockade of c-Jun or knockdown of c-Jun significantly reduced the UV irradiation-induced activation of CYR61 promoter and CYR61 gene expression. These data show that CYR61 is transcriptionally regulated by UV irradiation through transcription factor AP-1, and mediates altered collagen homeostasis that occurs in response to UV irradiation in human skin fibroblasts.

Oxidative Stress and Human Skin Connective Tissue Aging

“…CCN1 is also significantly induced by acute UV irradiation in human skin in vivo, and in UV-irradiated human dermal fibroblasts in vitro [77,78]. CCN1 functions as a key mediator of UV-induced aberrant collagen homeostasis.…”

“…In human skin, CCN1 is predominantly expressed in dermal fibroblasts [38], and significantly elevated in dermal fibroblasts in aged human skin in vivo [38,39,77]. In cultured human dermal fibroblasts, the elevated expression of CCN1 not only inhibits the expression of type I procollagen, but also concurrently increases the expression of multiple MMPs and cytokines [36,38,39,77].…”

“…In cultured human dermal fibroblasts, the elevated expression of CCN1 not only inhibits the expression of type I procollagen, but also concurrently increases the expression of multiple MMPs and cytokines [36,38,39,77].…”

Cysteine-rich Protein 61 (CCN1) Domain-specific Stimulation of Matrix Metalloproteinase-1 Expression through αVβ3 Integrin in Human Skin Fibroblasts

“…In cell culture models, CCN1 recombinant protein regulates cell adhesion, cell migration, cell-matrix interactions, and the synthesis of extracellular matrix (24 -26). Furthermore, elevated CCN1 up-regulates MMP-1 protein expression in cultured primary human skin dermal fibroblasts (22,23).…”

“…CCN proteins play fundamental roles in growth, differentiation, angiogenesis, migration, and extracellular matrix regulation (19,21). We previously reported that CCN1 is expressed in human skin dermis and is substantially elevated in the dermis of naturally aged, photoaged, and acutely UV-irradiated human skin (22,23). In cell culture models, CCN1 recombinant protein regulates cell adhesion, cell migration, cell-matrix interactions, and the synthesis of extracellular matrix (24 -26).…”