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CCN2 induces cellular senescence in fibroblasts

  • RESEARCH ARTICLE
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Journal of Cell Communication and Signaling Aims and scope

Abstract

The expression of Ccn2 (CTGF) has been linked to fibrosis in many tissues and pathologies, although its activities in fibroblastic cells and precise mechanism of action in fibrogenesis are still controversial. Here, we showed that CCN2 can induce cellular senescence in fibroblasts both in vitro and in vivo, whereupon senescent cells express an anti-fibrotic “senescence-associated secretory phenotype” (SASP) that includes upregulation of matrix metalloproteinases and downregulation of collagen. Mechanistically, CCN2 induces fibroblast senescence through integrin α6β1-mediated accumulation of reactive oxygen species, leading to activation of p53 and induction of p16INK4a. In cutaneous wound healing, Ccn2 expression is highly elevated only during the initial inflammatory phase and quickly declines thereafter to a low level during the proliferation and maturation phases of healing when myofibroblasts play a major role. Consistent with this expression kinetics, knockdown of Ccn2 has little effect on the rate of wound closure, formation of senescent cells, or collagen content of the wounds. However, application of purified CCN2 protein on cutaneous wounds leads to induction of senescent cells, expression of SASP, and reduction of collagen content. These results show that CCN2 can induce cellular senescence in fibroblasts and is capable of exerting an anti-fibrotic effect in a context-dependent manner.

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Acknowledgments

We are grateful to Dr. Woo Jin Park for gifts of adenoviral vectors. This work was supported by a grant from the NIH (R01 AR061791) to L.F.L.

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  1. Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL, 60607, USA

    Joon-II Jun & Lester F. Lau

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  1. Joon-II Jun
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  2. Lester F. Lau
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Correspondence to Lester F. Lau.

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Jun, JI., Lau, L.F. CCN2 induces cellular senescence in fibroblasts. J. Cell Commun. Signal. 11, 15–23 (2017). https://doi.org/10.1007/s12079-016-0359-1

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  • DOI: https://doi.org/10.1007/s12079-016-0359-1

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