Background/Purpose:

Casein kinase-2 (CK2) is a highly conserved serine/threonine kinase. CK2 is a tetramer composed of 2 catalytic subunits (α or α’) and 2 β regulatory subunits, which are essential for cell viability. CK2 is discussed as a target for cancer therapy and is currently evaluated in clinical trials. Recently, we have shown that targeting of JAK2 might be an interesting molecular approach for the treatment of systemic sclerosis (SSc).

Methods:

Activation of CK2, JAK2, and STAT3 in human skin and in experimental fibrosis were determined by immunohistochemical analysis. CK2 signaling was inhibited by the selective CK2 inhibitor 4, 5, 6, 7-Tetrabromobenzotriazole (TBB). The mouse models of bleomycin-induced and TGF-β receptor I (TBR)-induced dermal fibrosis were used to evaluate the anti-fibrotic potential of specific CK2 inhibition in vivo.

Results:

Increased expression of CK2 was detected by immunohistochemistry in skin sections of SSc patients, particularly in fibroblasts. Inhibition of CK2 by TBB in cultured fibroblasts completely abrogated the stimulatory effects of TGFβ on collagen release (p<0.05). After TBB treatment, stress fiber formation and α-smooth muscle actin (α-SMA) expression in TGFβ-stimulated fibroblasts were significantly reduced by 97% (p=0.0064) and 69% (p=0.0280). Besides reduced fibroblast activation, western blot analyses showed complete normalization of the levels of phosphorylated JAK2 (pJAK2) in the cytoplasm and of phosphorylated STAT3 (pSTAT3) in the nucleus of TGFβ-treated fibroblasts upon pre-incubation with TBB (p=0.0004 and p=0.0214). In addition, treatment with TBB effectively prevented bleomycin-induced fibrosis in mice with decreased dermal thickness by up to 70% (p<0.0001) and efficient reductions in myofibroblast counts by up to 68% (p=0.0002). TBR-induced fibrosis in mice was strongly ameliorated by TBB with efficient reductions of dermal thickening by 75% (p<0.0001). Myofibroblast counts and hydroxyproline content also decreased by 59% and 40% (p<0.0001 and p=0.0193), respectively. In both murine models, we observed reduced pJAK2 and pSTAT3 expression as analyzed by immunohistochemistry.

Conclusion:

We demonstrate that CK2 is activated in SSc and prove that inhibition of CK2 reduces canonical TGF-β signaling and prevents experimental fibrosis in different preclinical models. Considering the potent anti-fibrotic effects of CK2 inhibition, our study might have direct translational implications. These data provide first evidence that targeting CK2 may be a novel therapeutic approach for fibrotic diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-casein-kinase-ii-reduces-tgf%ce%b2-induced-fibroblast-activation-and-ameliorates-experimental-fibrosis/