Abstract
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-β fibrotic responses in a Smad-independent manner. Pharmacological inhibitors of CDK5 likewise prevented and reversed TGF-β 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.
Highlights
Systemic sclerosis (SSc) is associated with multiorgan fibrosis [1]
Because expression of p35 largely determines the level of Cyclin-dependent kinase 5 (CDK5) activity, we investigated the effect of transforming growth factor-ß (TGF-ß) on CDK5 phosphorylation and activity
These results indicate that the CDK5 activator subunit p35 is elevated in human and mouse skin fibrosis, its expression is induced by TGF-ß in a Smad-dependent manner, and it mediates enhanced CDK5 activity in TGFß-treated fibroblasts
Summary
A hallmark of SSc, is attributed to phenoconversion of tissue-resident mesenchymal progenitor cells to myofibroblasts, which produce extracellular matrix molecules, exert traction forces resulting in stiffness and extensive matrix remodeling, and resist apoptosis. Studies indicate that a variety of mesenchymal progenitor cells, including pericytes and adipocytes may give rise to fibrotic myofibroblasts in response to transforming growth factor-ß (TGF-ß), Wnt ligands and developmental pathways, hypoxia, and substrate rigidity [2]. Impaired expression or function of the adipogenic master regulator PPAR-γ facilitates fibroblast activation and myofibroblast phenoconversion, and contributes to persistence of fibrosis in the skin [3,4,5]. The factors that orchestrate wound healing and their deregulation resulting in non-resolving fibrosis are of www.impactjournals.com/oncotarget substantial interest, and represent potential therapeutic targets [2, 6]
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