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ADAMTS5 as a therapeutic target for osteoarthritis: Mendelian randomisation study
  1. Sizheng Steven Zhao1,
  2. Ville Karhunen2,3,
  3. Andrew P Morris4,
  4. Dipender Gill5,6,7
  1. 1 Centre for Epidemiology Versus Arthritis, University of Manchester, Manchester, UK
  2. 2 Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
  3. 3 Center for Life Course Health Research, University of Oulu, Oulu, Finland
  4. 4 Centre for Genetics and Genomics Versus Arthritis, University of Manchester, Manchester, UK
  5. 5 Clinical Pharmacology and Therapeutics Section, Institute for Infection and Immunity, St George’s, University of London, London, UK
  6. 6 Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George’s University Hospitals NHS Foundation Trust, London, UK
  7. 7 Department of Epidemiology and Biostatistics, Imperial College London, London, UK
  1. Correspondence to Dr Sizheng Steven Zhao, Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Science, Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; sizheng.zhao{at}manchester.ac.uk

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Osteoarthritis (OA) is a progressive disease for which there is no effective disease-modifying therapy. It is characterised by articular cartilage degradation with uncontrolled proteolytic extracellular matrix destruction. The major proteoglycan in the extracellular matrix—aggrecan—is primarily cleaved by the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of genes.1 ADAMTS5 knockout mice have less severe cartilage destruction after induced joint instability compared with wild-type counterparts.2 However, ADAMTS5 regulation differs in humans,1 for whom the therapeutic role of ADAMTS5 inhibition is yet unclear. Although several ADAMTS5 inhibitors have been patented, the sole phase II trial (NCT03595618) did not demonstrate benefit for imaging or pain outcomes in knee OA.

Natural variation in the gene that encodes a protein drug target can offer insight into the clinical effects of perturbing that target pharmacologically.3 The random allocation of genetic variants at conception means that such Mendelian randomisation (MR) analyses are robust to the confounding and reverse causation that can hinder causal inference in traditional epidemiological study designs.4 As genetic proxies for …

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @stezhao, @dpsg108

  • Contributors All authors contributed to writing and interpretation and approved of the final draft for submission.

  • Funding SSZ is supported by a National Institute for Health Research Clinical Lectureship. VK is supported by the Academy of Finland Project 312123, and European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 848158. APM is supported by Versus Arthritis (grant reference 21754). DG is supported by the British Heart Foundation Research Centre of Excellence (RE/18/4/34215) at Imperial College London and by a National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St. George’s, University of London.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.