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2017 ; 11
(1
): 15-23
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CCN2 induces cellular senescence in fibroblasts
#MMPMID27752926
Jun JI
; Lau LF
J Cell Commun Signal
2017[Mar]; 11
(1
): 15-23
PMID27752926
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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 ?(6)?(1)-mediated accumulation of reactive oxygen species,
leading to activation of p53 and induction of p16(INK4a). 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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