Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Cyclin-dependent kinase 5 (CDK5), expressed primarily in the central nervous system, plays important roles in axonal guidance, dopaminergic signaling, neuronal migration, and pain sensing. Aberrant CDK5 function is implicated in neurodegenerative diseases including Alzheimer’s disease. In contrast to other cyclin-dependent kinases, binding of the non-cyclin activator p35 is sufficient to induce CDK5 activity. Recent studies reveal novel extra-neuronal role for in inflammation and metabolism. The nuclear receptor PPAR-γ, a master regulator of adipogenesis and adipokine production, is impaired in scleroderma. Since PPAR-γ is a novel CDK5 substrate, we hypothesized that the CDK5/p35 pathway might be responsible for impaired PPAR-γ function in SSc and play a role in the development and persistence of fibrosis.
Methods:
Expression of p35 was examined in skin biopsies from bleomycin-injected mice and explanted scleroderma fibroblasts. Regulation of p35/CDK5 expression and activity in vitro was examined in human and mouse skin fibroblasts, progenitor cells and mature adipocytes by real-time qPCR, Western analysis and in vitro kinase assays. Effects of CDK5/p35 loss-of-function and gain-of-function were evaluated in normal and scleroderma skin fibroblasts using monolayer cultured fibroblasts and ex vivo using human skin organ cultures. CDK5 inhibition was examined in vivo using mouse models of fibrosis induced by bleomycin or constitutively active Type I TGF-β receptor.
Results: Levels of p35 mRNA were markedly elevated in explanted scleroderma fibroblasts (n=6, p<0.005). p35 was also elevated in lesional skin from mice with bleomycin-induced scleroderma. Both p35 expression and CDK5 activity were strongly stimulated by TGF-β in human and mouse skin fibroblasts, mesenchymal progenitor cells and mature adipocytes. Ectopic p35 and CDK5 caused suppression of adiponectin expression and simultaneous stimulation of collagen synthesis in these cells, whereas RNAi-mediated knockdown of p35/CDK5 abrogated TGF-β-induced fibrotic gene expression. Pharmacological inhibitors of CDK5 not only prevented but even reversed TGF-β-induced fibrotic responses in monolayer cultures and in skin organ cultures, and ameliorated collagen overproduction in scleroderma fibroblasts. Moreover, CDK5 inhibitor prevented and reversed skin fibrosis in complementary inflammatory and TGF-ß-driven mouse models of scleroderma.
Conclusion:
The CDK5/p35 axis has a previously unrecognized important non-neuronal function in modulating fibrotic responses. Elevated p35 expression and CDK5 activity is an unexpected feature of scleroderma that might contribute to development of fibrosis. Pharmacological targeting CDK5/p35 might be novel treatment for fibrosis.
Disclosure:
J. Wei,
None;
R. G. Marangoni,
None;
W. Wang,
None;
J. Huang,
None;
J. H. W. Distler,
None;
J. Varga,
None.
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