{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:31:14Z","timestamp":1789644674272,"version":"4.0.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>One of the histologic characteristics of systemic sclerosis (SSc) is an increased number of dermal myofibroblasts, and transforming growth factor \u03b2 (TGF\u03b2) 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\u2010dependent 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 TGF\u03b2 receptor (TGF\u03b2R) inhibitor, on dermal fibrosis in murine models of SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fibroblasts obtained from the skin of patients with SSc were cultured in the presence or absence of TGF\u03b2. The effects of palbociclib, a CDK4\/6 inhibitor, on fibroblast proliferation and TGF\u03b2\u2010induced differentiation into myofibroblasts were examined using bromodeoxyuridine uptake assays as well as immunofluorescence and immunoblotting analyses. Murine models of HOCl\u2010 and bleomycin\u2010induced 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 TGF\u03b2R inhibitor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Addition of a CDK4\/6 inhibitor to the cell cultures suppressed the proliferation of human dermal SSc fibroblasts and their TGF\u03b2\u2010induced differentiation into myofibroblasts, without inhibiting canonical and noncanonical TGF\u03b2 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 TGF\u03b2R inhibitor resulted in additive antifibrotic effects. Mechanistically, the CDK4\/6 inhibitor suppressed the expression of cellular communication network 2 and cadherin\u201011, which are proteins that have important roles in the development and progression of fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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 TGF\u03b2R 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 TGF\u03b2R inhibitor, might result in increased efficacy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42042","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T07:34:24Z","timestamp":1639035264000},"page":"860-870","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Therapeutic Effect of <scp>Cyclin\u2010Dependent<\/scp> Kinase 4\/6 Inhibitor on Dermal Fibrosis in Murine Models of Systemic Sclerosis"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-6571","authenticated-orcid":false,"given":"Akio","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Tokyo Medical and Dental University  Tokyo 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