Evidence map›Paper›PMID 29566767›Full record

ArticleArthritis research & therapy2018

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

Kohjin Suzuki, Kohsuke Yoshida, Takeshi Ueha, Kenta Kaneshiro, Ayako Nakai, Naonori Hashimoto, Koto Uchida, Teppei Hashimoto, Yoshiko Kawasaki, Nao Shibanuma and 3 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Arthritis research & therapy, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed, 1 pooled it
0.9field-weighted citation impact, top 29% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 1 synthesis or guideline pooled it, 16 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Article
  4. Article
  5. Article
  6. Review
  7. Cell-Free DNA in Rheumatoid Arthritis.International journal of molecular sciences · 2021
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 1 country.

Kohjin SuzukiDepartment of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe, 654-0142, Japan.
Kohsuke YoshidaDepartment of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe, 654-0142, Japan.
Takeshi UehaDivision of Rehabilitation Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
Kenta KaneshiroDepartment of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe, 654-0142, Japan.
Ayako NakaiDepartment of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe, 654-0142, Japan.
Naonori HashimotoDepartment of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe, 654-0142, Japan.
Koto UchidaDepartment of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe, 654-0142, Japan.
Teppei HashimotoDepartment of Rheumatology, Kobe Kaisei Hospital, Kobe, 657-0068, Japan.
Yoshiko KawasakiDepartment of Rheumatology, Kobe Kaisei Hospital, Kobe, 657-0068, Japan.
Nao ShibanumaDepartment of Orthopedic Surgery, Kobe Kaisei Hospital, Kobe, 657-0068, Japan.
Natsuko NakagawaDepartment of Rheumatology, Hyogo Prefectural Kakogawa Medical Center, Kakogawa, 675-0003, Japan.
Yoshitada SakaiDivision of Rehabilitation Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
Akira HashiramotoDepartment of Biophysics, Kobe University Graduate School of Health Sciences, Tomogaoka 7-10-2, Suma-ku, Kobe, 654-0142, Japan. hash@med.kobe-u.ac.jp.
Kobe University · JPKobe Kaisei Hospital · JPEdogawa Hospital · JP

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundEffects 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.

methodsUnder 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.

resultsMTX (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.

conclusionsWe 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.

Indexed as

Antirheumatic AgentsApoptosisArthritis, RheumatoidCells, CulturedCircadian ClocksCircadian RhythmCollagen Type XIDose-Response Relationship, DrugFemaleFibroblastsHumansMaleMethotrexateMiddle AgedNuclear ProteinsRNA-Binding ProteinsALYREF protein, humanAntirheumatic AgentsCOL11A2 protein, humanCollagen Type XIMethotrexateNuclear ProteinsRNA-Binding ProteinsTranscription FactorsBcl-2 interacting killerMethotrexatePeriod2Proline and acidic amino acid-rich basic leucine zipperRheumatoid arthritisSynovial fibroblasts

Identifiers

PMID29566767
PMCPMC5863822
OpenAlexW2798008988

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.