Therapeutic Effect of Cyclin-Dependent Kinase 4/6 Inhibitor on Dermal Fibrosis in Murine Models of Systemic Sclerosis.

Abstract

OBJECTIVE:

One of the histologic characteristics of systemic sclerosis (SSc) is an increased number of dermal myofibroblasts, and transforming growth factor β (TGFβ) plays a crucial role in the promotion of myofibroblast differentiation from fibroblasts, leading to dermal fibrosis. This study was undertaken to 1) examine whether inhibition of the cell cycle with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor suppresses the proliferation of fibroblasts and their differentiation into myofibroblasts, and 2) assess the therapeutic effects of a CDK4/6 inhibitor, administered as monotherapy or in combination with a TGFβ receptor (TGFβR) inhibitor, on dermal fibrosis in murine models of SSc.

METHODS:

Fibroblasts obtained from the skin of patients with SSc were cultured in the presence or absence of TGFβ. The effects of palbociclib, a CDK4/6 inhibitor, on fibroblast proliferation and TGFβ-induced differentiation into myofibroblasts were examined using bromodeoxyuridine uptake assays as well as immunofluorescence and immunoblotting analyses. Murine models of HOCl- and bleomycin-induced dermal fibrosis were used to study the effect of a CDK4/6 inhibitor on dermal fibrosis, with the CDK4/6 inhibitor treatment administered as monotherapy or in combination with galunisertib, a TGFβR inhibitor.

RESULTS:

Addition of a CDK4/6 inhibitor to the cell cultures suppressed the proliferation of human dermal SSc fibroblasts and their TGFβ-induced differentiation into myofibroblasts, without inhibiting canonical and noncanonical TGFβ signals. In murine models of dermal fibrosis, treatment of mice with a CDK4/6 inhibitor decreased dermal thickness and collagen content, as well as dermal fibroblast proliferation and the numbers of myofibroblasts. Combination therapy with the CDK4/6 inhibitor and TGFβR inhibitor resulted in additive antifibrotic effects. Mechanistically, the CDK4/6 inhibitor suppressed the expression of cellular communication network 2 and cadherin-11, which are proteins that have important roles in the development and progression of fibrosis.

CONCLUSION:

Results of this study demonstrate the therapeutic effect of a CDK4/6 inhibitor on dermal fibrosis when administered as monotherapy or in combination with a TGFβR inhibitor. CDK4/6 inhibitors, including palbociclib used in the present study, may represent novel agents for the treatment of SSc, which, if used in combination with a TGFβR inhibitor, might result in increased efficacy.

• Authors: Akio Yamamoto, Tetsuya Saito, Tadashi Hosoya, Kimito Kawahata, Yoshihide Asano, Shinichi Sato, Fumitaka Mizoguchi, Shinsuke Yasuda, Hitoshi Kohsaka
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 74 Issue 5 Pg. 860-870 (05 2022) ISSN: 2326-5205 [Electronic] United States
• PMID: 34882985 (Publication Type: Journal Article)
• Copyright: © 2021 American College of Rheumatology.

Chemical References

• Protein Kinase Inhibitors
• Receptors, Transforming Growth Factor beta
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Cells, Cultured
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Disease Models, Animal
• Fibroblasts (metabolism)
• Fibrosis
• Humans
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Scleroderma, Systemic (pathology)
• Skin (pathology)