CDK6-Dependent, CDK4-Independent Synovial Hyperplasia in Arthritic Mice and Tumor Necrosis Factor-α-Induced Proliferation of Synovial Fibroblasts.

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.