Evidence map›Paper›PMID 27884645›Full record

ArticleOsteoarthritis and cartilage2017

Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-β signaling in chondrocytes.

R Akagi, Y Akatsu, K M Fisch, O Alvarez-Garcia, T Teramura, Y Muramatsu, M Saito, T Sasho, A I Su, M K Lotz

Open access · bronzeAbstract read
In one paragraph

Article in Osteoarthritis and cartilage, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.

0numbers the graph read from it
0cells of the map it votes in
55citing papers in PubMed
2.6field-weighted citation impact, top 11% 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

55 citing papers in PubMed, 103 citations in OpenAlex.

  1. The ClockJournal of orthopaedic surgery and research · 2026
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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

10 authors at 2 institutions in 2 countries.

R AkagiDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA; Department of Orthopaedic Surgery, School of Medicine, Chiba University, 1-8-1, Inohana, Chuou, Chiba, 260-8677, Japan.
Y AkatsuDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA; Department of Orthopaedic Surgery, School of Medicine, Chiba University, 1-8-1, Inohana, Chuou, Chiba, 260-8677, Japan.
K M FischDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA.
O Alvarez-GarciaDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA.
T TeramuraDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA.
Y MuramatsuDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA.
M SaitoDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA; Department of Orthopaedic Surgery, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan.
T SashoDepartment of Orthopaedic Surgery, School of Medicine, Chiba University, 1-8-1, Inohana, Chuou, Chiba, 260-8677, Japan.
A I SuDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA.
M K LotzDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA. Electronic address: mlotz@scripps.edu.
Scripps Research Institute · USChiba University · JP

Funding

TISSUE ACQUISITION, MORPHOLOGY, AND CELL CULTUREP01AG007996 · NIA · UNIVERSITY OF CALIFORNIA SAN DIEGO · PI LOTZ, MARTIN K · 1989 to 2016
$26.0M
Integrative Omics analysis of human cartilage in aging and osteoarthritisR01AG049617 · NIA · SCRIPPS RESEARCH INSTITUTE, THE · PI LOTZ, MARTIN K · 2016 to 2024
$5.6M
NIA NIH HHS P01 AG007996NIA NIH HHS R01 AG049617
6 · The paper itself

Abstract

objectivesCircadian rhythm (CR) was identified by RNA sequencing as the most dysregulated pathway in human osteoarthritis (OA) in articular cartilage. This study examined circadian rhythmicity in cultured chondrocytes and the role of the CR genes NR1D1 and BMAL1 in regulating chondrocyte functions.

methodsRNA was extracted from normal and OA-affected human knee cartilage (n = 14 each). Expression levels of NR1D1 and BMAL1 mRNA and protein were assessed by quantitative PCR and immunohistochemistry. Human chondrocytes were synchronized and harvested at regular intervals to examine circadian rhythmicity in RNA and protein expression. Chondrocytes were treated with small interfering RNA (siRNA) for NR1D1 or BMAL1, followed by RNA sequencing and analysis of the effects on the transforming growth factor beta (TGF-β) pathway.

resultsNR1D1 and BMAL1 mRNA and protein levels were significantly reduced in OA compared to normal cartilage. In cultured human chondrocytes, a clear circadian rhythmicity was observed for NR1D1 and BMAL1. Increased BMAL1 expression was observed after knocking down NR1D1, and decreased NR1D1 levels were observed after knocking down BMAL1. Sequencing of RNA from chondrocytes treated with NR1D1 or BMAL1 siRNA identified 330 and 68 significantly different genes, respectively, and this predominantly affected the TGF-β signaling pathway.

conclusionsThe CR pathway is dysregulated in OA cartilage. Interference with circadian rhythmicity in cultured chondrocytes affects TGF-β signaling, which is a central pathway in cartilage homeostasis.

Indexed as

AdolescentAdultARNTL Transcription FactorsCartilage, ArticularChondrocytesCircadian RhythmFemaleGene Expression RegulationGene Knockdown TechniquesHumansMaleMiddle AgedNuclear Receptor Subfamily 1, Group D, Member 1Osteoarthritis, KneeRNA, MessengerSignal TransductionARNTL Transcription FactorsBMAL1 protein, humanNR1D1 protein, humanNuclear Receptor Subfamily 1, Group D, Member 1RNA, MessengerTransforming Growth Factor betaBMAL1Circadian rhythmNR1D1OsteoarthritisTGF-β

Identifiers

PMID27884645
PMCPMC5438901
OpenAlexW2328777822

What OpenQuestion holds

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Read underepoch 390

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.