Komatsu Rie, Fujii Ryoji, Ogasawara Toru, Suzuki-Takahashi Yuki, Chen Sandy, Sugishita Yodo, Niki Hisateru, Yudoh Kazuo
Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Kanagawa, Japan.
Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Int J Mol Sci. 2025 Jan 28;26(3):1151. doi: 10.3390/ijms26031151.
Palbociclib, a dual CDK4/6 kinase inhibitor used for breast cancer, has been explored as a treatment option for rheumatoid arthritis (RA). Preclinical studies have reported palbociclib-induced myelosuppression, but no such effects have been observed in or single-deficient mice. Synoviocyte proliferation-associated in collagen-induced arthritis 1/serum amyloid A-like 1 (SPACIA1/SAAL1) is involved in G1 phase progression. Given that SPACIA1/SAAL1 upregulates (but not ) expression, we aimed to determine whether suppressing CDK6 expression alone could prevent synovial hyperplasia without myelosuppression. The effects of CDK6 expression on TNF-α-induced rheumatoid arthritis synovial fibroblast (RASF) proliferation and synovial hyperplasia in collagen-induced arthritis (CIA) mice were investigated by modulating the transcriptional level with a expression inhibitor (indole-3-carbinol), small interfering RNA (siRNA), and -deficient mice. Indole-3-carbinol or siRNA inhibited TNF-α-induced RASF proliferation without suppressing CDK4 expression and reduced retinoblastoma protein phosphorylation. In CIA mice, indole-3-carbinol did not cause myelosuppression, considerably delayed CIA onset and progression, and reduced arthritis severity. -deficient mice showed similar improvements in CIA pathogenesis but had lower serum anti-type II collagen IgG levels. Notably, synovial hyperplasia was not observed in -deficient mice. CIA-synovial hyperplasia depends on CDK6, but not CDK4, expression.
帕博西尼是一种用于治疗乳腺癌的双重CDK4/6激酶抑制剂，已被探索作为类风湿性关节炎（RA）的一种治疗选择。临床前研究报告了帕博西尼诱导的骨髓抑制，但在 或 单基因缺陷小鼠中未观察到此类效应。胶原诱导性关节炎1/血清淀粉样蛋白A样1（SPACIA1/SAAL1）相关的滑膜细胞增殖参与G1期进程。鉴于SPACIA1/SAAL1上调 （而非 ）表达，我们旨在确定单独抑制CDK6表达是否能预防滑膜增生而不引起骨髓抑制。通过用 表达抑制剂（吲哚 - 3 - 甲醇）、 小干扰RNA（siRNA）和 基因缺陷小鼠调节转录水平，研究了CDK6表达对肿瘤坏死因子 - α诱导的类风湿性关节炎滑膜成纤维细胞（RASF）增殖以及胶原诱导性关节炎（CIA）小鼠滑膜增生的影响。吲哚 - 3 - 甲醇或 siRNA抑制了肿瘤坏死因子 - α诱导的RASF增殖，而不抑制CDK4表达，并降低了视网膜母细胞瘤蛋白磷酸化水平。在CIA小鼠中，吲哚 - 3 - 甲醇未引起骨髓抑制，显著延迟了CIA的发病和进展，并减轻了关节炎严重程度。 基因缺陷小鼠在CIA发病机制方面表现出类似的改善，但血清抗II型胶原IgG水平较低。值得注意的是，在 基因缺陷小鼠中未观察到滑膜增生。CIA滑膜增生取决于CDK6的表达，而非CDK4的表达。
