University of Oulu

Mustonen, AM., Tollis, S., Käkelä, R. et al. Increased n-6 Polyunsaturated Fatty Acids Indicate Pro- and Anti-Inflammatory Lipid Modifications in Synovial Membranes with Rheumatoid Arthritis. Inflammation 46, 1396–1413 (2023).

Increased n-6 polyunsaturated fatty acids indicate pro- and anti-inflammatory lipid modifications in synovial membranes with rheumatoid arthritis

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Author: Mustonen, Anne-Mari1,2; Tollis, Sylvain1; Käkelä, Reijo3,4;
Organizations: 1Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
2Department of Environmental and Biological Sciences, Faculty of Science, Forestry and Technology, University of Eastern Finland, P.O. Box 111, FI-80101, Joensuu, Finland
3Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, P.O. Box 65, FI-00014, Helsinki, Finland
4Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute of Life Science (HiLIFE) and Biocenter Finland, University of Helsinki, P.O. Box 65, FI-00014, Helsinki, Finland
5Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland
6Medical Research Center, University of Oulu and Oulu University Hospital, P.O. Box 5000, FI-90014, Oulu, Finland
7Department of Surgery, Oulu University Hospital, P.O. Box 21, FI-90029, OYS, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.7 MB)
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Language: English
Published: Springer Nature, 2023
Publish Date: 2023-09-06


Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools.

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Series: Inflammation
ISSN: 0360-3997
ISSN-E: 1573-2576
ISSN-L: 0360-3997
Volume: 46
Issue: 4
Pages: 1396 - 1413
DOI: 10.1007/s10753-023-01816-3
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: Open access funding provided by University of Eastern Finland (UEF) including Kuopio University Hospital. Financial support for the study was provided by the Academy of Finland (grant #322429 to P.N.). Bioinformatics analyses were performed with funding from the Sigrid Jusélius Foundation (grant #220196 to S.T.). The funding sources had no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.
Copyright information: © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit