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2018 ; 9
(12
): 10294-10306
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The non-neuronal cyclin-dependent kinase 5 is a fibrotic mediator potentially
implicated in systemic sclerosis and a novel therapeutic target
#MMPMID29535807
Wei J
; Marangoni RG
; Fang F
; Wang W
; Huang J
; Distler JHW
; Varga J
Oncotarget
2018[Feb]; 9
(12
): 10294-10306
PMID29535807
show ga
The mechanisms underlying persistent fibroblast activation and myofibroblast
phenoconversion in underlying multi-organ fibrosis in systemic sclerosis (SSc)
remain incompletely understood, hindering effective therapies to slow or reverse
the process. Cyclin-dependent kinase 5 (CDK5) is a pleiotropic member of the CDK
family originally identified in neuronal cells. In contrast to other CDKs, CDK5
activity depends on its CDK5R1 subunit p35. Here we demonstrate that expression
of p35 and CDK5 activity are induced by TGF-ß in fibroblasts and adipocytic cell
types. Levels of p35 are markedly elevated in both SSc skin biopsies and
explanted SSc fibroblasts, as well as in fibrotic skin in mice. Ectopic p35 and
CDK5 suppressed adipogenic markers while stimulating collagen production and
myofibroblast markers, whereas RNAi-mediated CDK5 knockdown abrogated TGF-?
fibrotic responses in a Smad-independent manner. Pharmacological inhibitors of
CDK5 likewise prevented and reversed TGF-? responses in fibroblast monolayers and
in ex vivo human skin organ cultures, ameliorated collagen overproduction in SSc
fibroblasts, and prevented and reversed skin fibrosis in two distinct mouse
models of SSc. Together, these results reveal a previously unrecognized key
function for p35/CDK5 as a mediator of mesenchymal cell fibrotic responses. The
results suggest a potential pathogenic role for elevated p35 expression and CDK5
activity in SSc, and raise the possibility that their selective pharmacological
targeting might represent a novel treatment approach in fibrosis.
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