Obese osteoarthritis patients exhibit an inflammatory synovial fibroblast phenotype, which is regulated by the long non coding RNA MALAT1

Dominika E. Nanus, Susanne N. Wijesinghe, Mark J. Pearson, Marina R. Hadjicharalambous, Alex Rosser, Edward T. Davis, Mark Lindsay, Simon W. Jones

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To identify lncRNAs associated with the inflammatory phenotype of obese OA synovial fibroblasts and explore their expression and function. METHODS: Synovium was collected from normal-weight hip fracture non-OA patients (n=6) and from normal-weight (n=8) and obese hip OA patients (n=8). RNA expression was determined by RNA sequencing and qRT-PCR. LncRNA knockdown utilised LNA-based GapmeRs. Cytokine production was measured by ELISA. RESULTS: Synovial fibroblasts (n=6 patients) from obese OA patients secreted greater IL6 (162 ± 21 pg/ml; p<0.001) and CXCL8 (262 ± 67 pg/ml; p<0.05) than fibroblasts from normal-weight OA (51 ± 4 pg/ml IL6; 78 ± 11 pg/ml CXCL8) or from non-OA patients (35 ± 3 pg/ml IL6; 56 ± 6 pg/ml CXCL8). Sequencing (n=4 patients) revealed obese OA fibroblasts to exhibit an inflammatory transcriptome, with increased expression of pro-inflammatory mRNAs, compared to normal-weight OA or non-OA fibroblasts. 19 lncRNAs were differentially expressed between normal-weight OA and non-OA fibroblasts and a further 19 lncRNAs differentially expressed between obese OA and normal-weight OA fibroblasts (>2-fold, p<0.05), which included MALAT1. MALAT1 was rapidly induced upon pro-inflammatory cytokine stimulation and upregulated in obese OA synovium, compared to normal-weight OA (1.6-fold, p<0.001) or non-OA synovium (6-fold, p<0.001). MALAT1 knockdown in OA synovial fibroblasts (n=4 patients) decreased CXCL8 expression and secretion (>1.5-fold, p<0.01), increased TRIM6 (>2-fold, p<0.01), IL7R (<2-fold, p<0.01), HIST1H1C (>1.5-fold, p<0.001) and MAML3 (>1.5-fold, p<0.001) expression, and inhibited synovial fibroblast proliferation. CONCLUSION: Synovial fibroblasts from obese OA patients exhibit an inflammatory phenotype. MALAT1 lncRNA may mediate joint inflammation in obese OA patients.
Original languageEnglish
JournalArthritis & Rheumatology
Early online date4 Nov 2019
DOIs
Publication statusE-pub ahead of print - 4 Nov 2019

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Nanus, D. E., Wijesinghe, S. N., Pearson, M. J., Hadjicharalambous, M. R., Rosser, A., Davis, E. T., ... Jones, S. W. (2019). Obese osteoarthritis patients exhibit an inflammatory synovial fibroblast phenotype, which is regulated by the long non coding RNA MALAT1. Arthritis & Rheumatology. https://doi.org/10.1002/art.41158