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Background  Effects of methotrexate (MTX) on the proliferation of rheumatoid arthritis (RA) synovial fibroblasts are incompletely understood. We explored actions of MTX in view of circadian transcriptions of synovial fibroblasts.    Methods  Under treatment with MTX, expression of core circadian clock genes, circadian transcriptional factor proline and acidic amino acid-rich basic leucine zipper (PAR bZIP), and proapoptotic molecule Bcl-2 interacting killer (Bik) was examined by real-time polymerase chain reaction. Protein expression of circadian clock gene PERIOD2 (PER2) and CYTOCHROME C was also examined by western blotting and ELISA. Promoter activities of  Per2  and  Bik  were measured by Luciferase assay. Expression of PER2, BIK, and CYTOCHROME C and morphological changes of the nucleus were observed by fluorescent immunostaining. Synovial fibroblasts were transfected with  Per2 / Bik  small interfering RNA, and successively treated with MTX to determine cell viabilities. Finally, synovial fibroblasts were treated with MTX according to the oscillation of  Per2/Bik  expression.    Results  MTX (10 nM) significantly decreased cell viabilities, but increased messenger RNA expression of  Per2, Bik , and PAR ZIP including D site of the albumin promoter binding protein ( Dbp ), hepatic leukemia factor ( Hlf ), and thyrotroph embryonic factor ( Tef ). MTX also increased protein expression of PER2 and CYTOCHROME C, and promoter activities of  Per2  and  Bik via  D-box. Under fluorescent observations, expression of PER2, BIK, and CYTOCHROME C was increased in apoptotic cells. Cytotoxicity of MTX was attenuated by silencing of  Per2  and/or  Bik , and revealed that MTX was significantly effective in situations where  Per2 / Bik  expression was high.    Conclusions  We present here novel unique action of MTX on synovial fibroblasts that upregulates PAR bZIP to transcribe  Per2  and  Bik , resulting in apoptosis induction. MTX is important in modulating circadian environments to understand a new aspect of pathogenesis of RA.    Electronic supplementary material  The online version of this article (10.1186/s13075-018-1552-9) contains supplementary material, which is available to authorized users.

Methotrexate upregulates circadian transcriptional factors PAR bZIP to induce apoptosis on rheumatoid arthritis synovial fibroblasts