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The non-coding RNA interactome in joint health and disease

Abstract

Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that ‘non-coding’ does not mean ‘non-essential’ and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA.

Key points

  • An increasing body of literature on non-coding RNAs in joint health and disease has revealed important regulatory functions that indicate that ‘non-coding’ does not equate to ‘non-essential’.

  • Non-coding RNAs, including microRNAs, long non-coding RNAs and circular RNAs, can directly interact and have co-regulatory functions.

  • In osteoarthritis and rheumatoid arthritis, non-coding RNAs are important contributors to pathogenesis and serve as potential biomarkers and therapeutic targets.

  • With the emergence of data from high-throughput studies, detailed reporting and accurate annotation of results are required to integrate individual studies and enable interrogation of the non-coding RNA interactome.

  • An expanded understanding of the non-coding RNA interactome could reveal essential regulatory mechanisms and novel therapeutic opportunities for osteoarthritis, rheumatoid arthritis and other related joint diseases.

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Fig. 1: Biogenesis and function of microRNAs, long non-coding RNAs and circular RNAs.

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Acknowledgements

The work of M.J.P. is supported by a Wellcome Trust Intermediate Clinical Fellowship (107471/Z/15/Z) and by the Medical Research Council and Versus Arthritis as part of the Medical Research Council Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing (MR/R502182/1). The work of M.J.O. is supported by the Veterans Health Administration CDA (IK2CX001269) and by an Arthritis Foundation Delivering on Discovery grant. I.J. is also at the Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Ontario, Canada and the Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia. The work of I.J. was funded in part by the Ontario Research Fund (no. 34876 and GL2-01-030), the Natural Sciences Research Council (NSERC no. 203475), Genome Canada (DIG2 no. 14408), the Canada Foundation for Innovation (CFI no. 29272, no. 225404, no. 33536) and the Canada Research Chair Program (CRC no. 203373 and no. 225404). Additional support is provided by the Schroeder Arthritis Institute via the Toronto General and Western Hospital Foundation, University Health Network. The work of M.K. is supported by the Canadian Institute of Health Research Operating grant (no. 156299) and the Tier 1 Canada Research Chair Award (no. 950-232237).

Review criteria

A literature search was performed in PubMed for articles published in the past 2 years using combinations of the following key words: “osteoarthritis”, “rheumatoid arthritis”, “microRNA”, “long non-coding RNA”, “circular RNA”, “small nucleolar RNAs” and “transfer RNAs”. Some highly relevant papers outside the search criteria were also included.

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Correspondence to Shabana A. Ali or Mohit Kapoor.

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S.A.A. and M.K. declare that they have filed a US Provisional Patent Application no. 63/033,463 titled “Circulating MicroRNAs in Knee Osteoarthritis and Uses Thereof”. The other authors declare no competing interests.

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Related links

circAtlas: http://159.226.67.237:8080/new/index.php

circBase: http://www.circbase.org/

DIANA-lncBase: https://diana.e-ce.uth.gr/lncbasev3

EMBL-EBI European Nucleotide Archive: https://www.ebi.ac.uk/ena/browser/home

Enrichr: https://maayanlab.cloud/Enrichr/

Gene Ontology Resource: http://geneontology.org

Hugo Gene Nomenclature: https://www.genenames.org/

miRanda: https://bioweb.pasteur.fr/packages/pack@miRanda@3.3a

miRbase: http://www.mirbase.org/

miRDB: http://mirdb.org/

miRDeep2: https://github.com/rajewsky-lab/mirdeep2

mirDIP: http://ophid.utoronto.ca/mirDIP/

NCBI Database of Genotypes and Phenotypes: https://www.ncbi.nlm.nih.gov/gap/

NCBI Gene Expression Omnibus repository: https://www.ncbi.nlm.nih.gov/gds

NCBI Sequence Read Archive: https://www.ncbi.nlm.nih.gov/sra

pathDIP: http://ophid.utoronto.ca/pathDIP/

TargetScan: http://www.targetscan.org/vert_72/

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Ali, S.A., Peffers, M.J., Ormseth, M.J. et al. The non-coding RNA interactome in joint health and disease. Nat Rev Rheumatol 17, 692–705 (2021). https://doi.org/10.1038/s41584-021-00687-y

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