Regulation of the inflammatory synovial fibroblast phenotype by metastasis‐associated lung adenocarcinoma transcript 1 long noncoding RNA in obese patients with osteoarthritis

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Regulation of the inflammatory synovial fibroblast phenotype by metastasis‐associated lung adenocarcinoma transcript 1 long noncoding RNA in obese patients with osteoarthritis. / Nanus, Dominika; Wijesinghe, Susanne; Pearson, Mark; Hadjicharalambous, Marina; Rosser, Alex; Davis, Edward; Lindsay, Mark; Jones, Simon.

In: Arthritis and Rheumatology, Vol. 72, No. 4, 01.04.2020, p. 609-619.

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@article{35272e2206d84289a933a37b012399a2,
title = "Regulation of the inflammatory synovial fibroblast phenotype by metastasis‐associated lung adenocarcinoma transcript 1 long noncoding RNA in obese patients with osteoarthritis",
abstract = "Objective: To identify long noncoding RNAs (lncRNAs) associated with the inflammatory phenotype of synovial fibroblasts from obese patients with osteoarthritis (OA), and to explore the expression and function of these lncRNAs.Methods: Synovium was collected from normal‐weight patients with hip fracture (non‐OA; n = 6) and from normal‐weight (n = 8) and obese (n = 8) patients with hip OA. Expression of RNA was determined by RNA‐sequencing and quantitative reverse transcription–polymerase chain reaction. Knockdown of lncRNA was performed using LNA‐based GapmeRs. Synovial fibroblast cytokine production was measured by enzyme‐linked immunosorbent assay.Results: Synovial fibroblasts from obese patients with OA secreted greater levels of interleukin‐6 (IL‐6) (mean ± SEM 162 ± 21 pg/ml; P < 0.001) and CXCL8 (262 ± 67 pg/ml; P < 0.05) compared to fibroblasts from normal‐weight patients with OA (IL‐6, 51 ± 4 pg/ml; CXCL8, 78 ± 11 pg/ml) or non‐OA patients (IL‐6, 35 ± 3 pg/ml; CXCL8, 56 ± 6 pg/ml) (n = 6 patients per group). RNA‐sequencing revealed that fibroblasts from obese OA patients exhibited an inflammatory transcriptome, with increased expression of proinflammatory messenger RNAs (mRNAs) as compared to that in fibroblasts from normal‐weight OA or non‐OA patients (>2‐fold change, P < 0.05; n = 4 patients per group). A total of 19 lncRNAs were differentially expressed between normal‐weight OA and non‐OA patient fibroblasts, and a further 19 lncRNAs were differentially expressed in fibroblasts from obese OA patients compared to normal‐weight OA patients (>2‐fold change, P < 0.05 for each), which included the lncRNA for metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1 was rapidly induced upon stimulation of OA synovial fibroblasts with proinflammatory cytokines, and was up‐regulated in the synovium from obese OA patients as compared to normal‐weight OA patients (1.6‐fold change, P < 0.001) or non‐OA patients (6‐fold change, P < 0.001). MALAT1 knockdown in OA synovial fibroblasts (n = 4 patients) decreased the levels of mRNA expression and protein secretion of CXCL8 (>1.5‐fold change, P < 0.01), whereas it increased expression of mRNAs for TRIM6 (>2‐fold change, P < 0.01), IL7R (<2‐fold change, P < 0.01), HIST1H1C (>1.5‐fold change, P < 0.001), and MAML3 (>1.5‐fold change, P < 0.001). In addition, MALAT1 knockdown inhibited the proliferation of synovial fibroblasts from obese patients with OA.Conclusion: Synovial fibroblasts from obese patients with hip OA exhibit an inflammatory phenotype. MALAT1 lncRNA may mediate joint inflammation in obese OA patients.",
author = "Dominika Nanus and Susanne Wijesinghe and Mark Pearson and Marina Hadjicharalambous and Alex Rosser and Edward Davis and Mark Lindsay and Simon Jones",
year = "2020",
month = apr,
day = "1",
doi = "10.1002/art.41158",
language = "English",
volume = "72",
pages = "609--619",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "Wiley",
number = "4",

}

RIS

TY - JOUR

T1 - Regulation of the inflammatory synovial fibroblast phenotype by metastasis‐associated lung adenocarcinoma transcript 1 long noncoding RNA in obese patients with osteoarthritis

AU - Nanus, Dominika

AU - Wijesinghe, Susanne

AU - Pearson, Mark

AU - Hadjicharalambous, Marina

AU - Rosser, Alex

AU - Davis, Edward

AU - Lindsay, Mark

AU - Jones, Simon

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Objective: To identify long noncoding RNAs (lncRNAs) associated with the inflammatory phenotype of synovial fibroblasts from obese patients with osteoarthritis (OA), and to explore the expression and function of these lncRNAs.Methods: Synovium was collected from normal‐weight patients with hip fracture (non‐OA; n = 6) and from normal‐weight (n = 8) and obese (n = 8) patients with hip OA. Expression of RNA was determined by RNA‐sequencing and quantitative reverse transcription–polymerase chain reaction. Knockdown of lncRNA was performed using LNA‐based GapmeRs. Synovial fibroblast cytokine production was measured by enzyme‐linked immunosorbent assay.Results: Synovial fibroblasts from obese patients with OA secreted greater levels of interleukin‐6 (IL‐6) (mean ± SEM 162 ± 21 pg/ml; P < 0.001) and CXCL8 (262 ± 67 pg/ml; P < 0.05) compared to fibroblasts from normal‐weight patients with OA (IL‐6, 51 ± 4 pg/ml; CXCL8, 78 ± 11 pg/ml) or non‐OA patients (IL‐6, 35 ± 3 pg/ml; CXCL8, 56 ± 6 pg/ml) (n = 6 patients per group). RNA‐sequencing revealed that fibroblasts from obese OA patients exhibited an inflammatory transcriptome, with increased expression of proinflammatory messenger RNAs (mRNAs) as compared to that in fibroblasts from normal‐weight OA or non‐OA patients (>2‐fold change, P < 0.05; n = 4 patients per group). A total of 19 lncRNAs were differentially expressed between normal‐weight OA and non‐OA patient fibroblasts, and a further 19 lncRNAs were differentially expressed in fibroblasts from obese OA patients compared to normal‐weight OA patients (>2‐fold change, P < 0.05 for each), which included the lncRNA for metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1 was rapidly induced upon stimulation of OA synovial fibroblasts with proinflammatory cytokines, and was up‐regulated in the synovium from obese OA patients as compared to normal‐weight OA patients (1.6‐fold change, P < 0.001) or non‐OA patients (6‐fold change, P < 0.001). MALAT1 knockdown in OA synovial fibroblasts (n = 4 patients) decreased the levels of mRNA expression and protein secretion of CXCL8 (>1.5‐fold change, P < 0.01), whereas it increased expression of mRNAs for TRIM6 (>2‐fold change, P < 0.01), IL7R (<2‐fold change, P < 0.01), HIST1H1C (>1.5‐fold change, P < 0.001), and MAML3 (>1.5‐fold change, P < 0.001). In addition, MALAT1 knockdown inhibited the proliferation of synovial fibroblasts from obese patients with OA.Conclusion: Synovial fibroblasts from obese patients with hip OA exhibit an inflammatory phenotype. MALAT1 lncRNA may mediate joint inflammation in obese OA patients.

AB - Objective: To identify long noncoding RNAs (lncRNAs) associated with the inflammatory phenotype of synovial fibroblasts from obese patients with osteoarthritis (OA), and to explore the expression and function of these lncRNAs.Methods: Synovium was collected from normal‐weight patients with hip fracture (non‐OA; n = 6) and from normal‐weight (n = 8) and obese (n = 8) patients with hip OA. Expression of RNA was determined by RNA‐sequencing and quantitative reverse transcription–polymerase chain reaction. Knockdown of lncRNA was performed using LNA‐based GapmeRs. Synovial fibroblast cytokine production was measured by enzyme‐linked immunosorbent assay.Results: Synovial fibroblasts from obese patients with OA secreted greater levels of interleukin‐6 (IL‐6) (mean ± SEM 162 ± 21 pg/ml; P < 0.001) and CXCL8 (262 ± 67 pg/ml; P < 0.05) compared to fibroblasts from normal‐weight patients with OA (IL‐6, 51 ± 4 pg/ml; CXCL8, 78 ± 11 pg/ml) or non‐OA patients (IL‐6, 35 ± 3 pg/ml; CXCL8, 56 ± 6 pg/ml) (n = 6 patients per group). RNA‐sequencing revealed that fibroblasts from obese OA patients exhibited an inflammatory transcriptome, with increased expression of proinflammatory messenger RNAs (mRNAs) as compared to that in fibroblasts from normal‐weight OA or non‐OA patients (>2‐fold change, P < 0.05; n = 4 patients per group). A total of 19 lncRNAs were differentially expressed between normal‐weight OA and non‐OA patient fibroblasts, and a further 19 lncRNAs were differentially expressed in fibroblasts from obese OA patients compared to normal‐weight OA patients (>2‐fold change, P < 0.05 for each), which included the lncRNA for metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1 was rapidly induced upon stimulation of OA synovial fibroblasts with proinflammatory cytokines, and was up‐regulated in the synovium from obese OA patients as compared to normal‐weight OA patients (1.6‐fold change, P < 0.001) or non‐OA patients (6‐fold change, P < 0.001). MALAT1 knockdown in OA synovial fibroblasts (n = 4 patients) decreased the levels of mRNA expression and protein secretion of CXCL8 (>1.5‐fold change, P < 0.01), whereas it increased expression of mRNAs for TRIM6 (>2‐fold change, P < 0.01), IL7R (<2‐fold change, P < 0.01), HIST1H1C (>1.5‐fold change, P < 0.001), and MAML3 (>1.5‐fold change, P < 0.001). In addition, MALAT1 knockdown inhibited the proliferation of synovial fibroblasts from obese patients with OA.Conclusion: Synovial fibroblasts from obese patients with hip OA exhibit an inflammatory phenotype. MALAT1 lncRNA may mediate joint inflammation in obese OA patients.

U2 - 10.1002/art.41158

DO - 10.1002/art.41158

M3 - Article

VL - 72

SP - 609

EP - 619

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 4

ER -