Development of methodology to support molecular endotype discovery from synovial fluid of individuals with knee osteoarthritis: The STEpUP OA consortium.

Autor: Deng Y; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom., Perry TA; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom., Hulley P; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom., Maciewicz RA; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom., Mitchelmore J; Novartis Institutes for Biomedical Research, Basel, Switzerland., Perry D; SomaLogic, Boulder, Colorado, United States of America., Larsson S; Department of Clinical Sciences Lund, Orthopaedics, Faculty of Medicine, Lund University, Lund, Sweden., Brachat S; Novartis Institutes for Biomedical Research, Basel, Switzerland., Struglics A; Department of Clinical Sciences Lund, Orthopaedics, Faculty of Medicine, Lund University, Lund, Sweden., Appleton CT; Bone and Joint Institute, University of Western Ontario, London, Ontario, Canada., Kluzek S; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.; NIHR Nottingham Biomedical Research Centre and Versus Arthritis Sport, Exercise and Osteoarthritis Centre, University of Nottingham, Nottingham, United Kingdom., Arden NK; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.; Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis, University of Oxford, Oxford, United Kingdom., Felson D; Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts, United States of America., Marsden B; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Tom BDM; MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom., Bondi L; MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom., Kapoor M; Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada., Batchelor V; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom., Mackay-Alderson J; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom., Kumar V; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom., Lohmander LS; Department of Clinical Sciences Lund, Orthopaedics, Faculty of Medicine, Lund University, Lund, Sweden., Welting TJ; Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, Maastricht, Netherlands., Walsh DA; Pain Centre Versus Arthritis, Advanced Pain Discovery Platform, and the NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom.; Sherwood Forest Hospitals NHS Foundation Trust, Sutton in Ashfield, United Kingdom., Valdes AM; Pain Centre Versus Arthritis, Advanced Pain Discovery Platform, and the NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom., Vincent TL; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom., Watt FE; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom.; Department of Immunology and Inflammation, Imperial College London, London, United Kingdom., Jostins-Dean L; Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Nov 18; Vol. 19 (11), pp. e0309677. Date of Electronic Publication: 2024 Nov 18 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0309677
Abstrakt: Objectives: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis.
Methods: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis.
Results: A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an 'intracellular protein score' (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space.
Conclusions: We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge.
Competing Interests: YD, TAP, PH, SL, AS, NKA, DF, BM, AMV, SK, VB, JMA and VK declare no conflicts of interest. FW has received consultancy fees from Pfizer, and has a leadership role at the Medical Research Council (panel member) and Osteoarthritis and Cartilage (Associate Editor). LSL has received consultancy fees from Arthro Therapeutics AB, and is an advisory board member of AstraZeneca (non consortium member). LJD has received consultancy fees from Nightingale Health PLC. TLV has no conflicts to declare with the exception of grant income for STEpUP OA from industry partners (see above). RAM is a shareholder of AstraZeneca. SB and JM are employees and shareholders of Novartis (consortium members). MK has received support for attending the Gordon Research Conference, OARSI meeting, International Cartilage Repair Society, Munster University, is a board member of the Dutch Arthritis Society (Chair of Visitation Board), and has a leadership role at Osteoarthritis Research Society International (Board of Directors Member). CTA has received consultancy fees from Novartis, and has received honoraria for educational purposes also from Novartis. DAW has received consultancy fees from GlaxoSmithKline plc, AKL Research & Development Limited, Pfizer Ltd, Eli Lilly and Company, Contura International, and AbbVie Inc, has received honoraria for educational purposes from Pfizer Ltd and AbbVie Inc, is a board member of UKRI (Director) and Versus Arthritis Advanced Pain Discovery Platform. “This does not alter our adherence to PLOS ONE policies on sharing data and materials (see also Data Availability statement)”.
(Copyright: © 2024 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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