Histology of systemic sclerosis (SSc) includes an increased number of myofibroblasts, where transforming growth factor-β (TGF-β) plays a crucial role to promote dermal fibrosis. The objectives of this study were to examine whether the inhibition of cell cycle with cyclin-dependent kinase (CDK) 4/6 inhibitor suppress fibroblast proliferation and the differentiation into myofibroblasts, and the therapeutic effect of a CDK4/6 inhibitor on dermal fibrosis in murine models of SSc in monotherapy or in combination with TGF-β receptor inhibitor (TGFβRI).
SSc fibroblasts were cultured in the presence or absence of TGF-β. Effects of palbociclib (CDKI), a CDK4/6 inhibitor, on fibroblast proliferation and TGF-β-induced differentiation into myofibroblasts were examined with BrdU uptake, immunofluorescence, and immunoblotting. Hypochlorous acid (HOCl)- and bleomycin-induced dermal fibrosis models were used to study the effect of CDKI on dermal fibrosis in monotherapy or in combination with galunisertib, a TGFβRI.
CDKI suppressed the proliferation of SSc fibroblasts and their TGF-β-induced differentiation into myofibroblast without inhibiting canonical and non-canonical TGF-β signals. Treatment of dermal fibrosis models with CDKI decreased dermal thickness and collagen content, as well as fibroblast proliferation and myofibroblast number. The combination therapy with CDKI and TGFβRI exerted additive anti-fibrotic effects. Mechanistically, CDKI suppressed the expression of cellular communication network (CCN) 2 and cadherin-11 important for fibrosis.
We demonstrated the therapeutic effect of CDKI on dermal fibrosis in monotherapy or in combination with TGFβRI. CDKI should be a novel agent for the treatment of SSc, which may be used with TGFβRI to increase the efficacy.