Metabolomics in the development and progression of rheumatoid arthritis: A systematic review

Li, Cheng; Chen, Bin; Fang, Zhen; Leng, Yu-fei; Wang, Danwen; Fengqin, Chen; Xu, Xiao; Sun, Zilin

doi:10.1016/j.jbspin.2020.05.005

Cited by 45 publications

(41 citation statements)

References 53 publications

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“…The expression of the Irg1 gene was accordingly higher in the hind limb tissue from transgenic animals relative to wild-type ( 138 ). This study also found higher levels of citrate in synovial fibroblasts of the transgenic mice compared with wild-type, in opposition to the decreased citrate seen in patient studies ( 136 , 138 ). The differences in these studies may represent different disease mechanisms, as well as distinct mechanisms of action of conventional DMARDs and the anti-TNF biologic.…”

Section: Tca Cycle Metabolitescontrasting

confidence: 81%

“…Despite the accumulation of citrate in inflammatory macrophages in vitro and peripheral blood T cells from RA patients, levels of citrate were found to be significantly reduced in synovial fluid, serum and urine samples from RA patients in comparison with healthy individuals ( 89 , 136 ). The decrease in synovial fluid citrate was linked to decreased expression of citrate synthase in RA patient synovial tissue.…”

Section: Tca Cycle Metabolitesmentioning

confidence: 87%

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Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

et al. 2021

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Mitochondria are major energy-producing organelles that have central roles in cellular metabolism. They also act as important signalling hubs, and their dynamic regulation in response to stress signals helps to dictate the stress response of the cell. Rheumatoid arthritis is an inflammatory and autoimmune disease with high prevalence and complex aetiology. Mitochondrial activity affects differentiation, activation and survival of immune and non-immune cells that contribute to the pathogenesis of this disease. This review outlines what is known about the role of mitochondria in rheumatoid arthritis pathogenesis, and how current and future therapeutic strategies can function through modulation of mitochondrial activity. We also highlight areas of this topic that warrant further study. As producers of energy and of metabolites such as succinate and citrate, mitochondria help to shape the inflammatory phenotype of leukocytes during disease. Mitochondrial components can directly stimulate immune receptors by acting as damage-associated molecular patterns, which could represent an initiating factor for the development of sterile inflammation. Mitochondria are also an important source of intracellular reactive oxygen species, and facilitate the activation of the NLRP3 inflammasome, which produces cytokines linked to disease symptoms in rheumatoid arthritis. The fact that mitochondria contain their own genetic material renders them susceptible to mutation, which can propagate their dysfunction and immunostimulatory potential. Several drugs currently used for the treatment of rheumatoid arthritis regulate mitochondrial function either directly or indirectly. These actions contribute to their immunomodulatory functions, but can also lead to adverse effects. Metabolic and mitochondrial pathways are attractive targets for future anti-rheumatic drugs, however many questions still remain about the precise role of mitochondrial activity in different cell types in rheumatoid arthritis.

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Section: Tca Cycle Metabolitescontrasting

confidence: 81%

Section: Tca Cycle Metabolitesmentioning

confidence: 87%

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

et al. 2021

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“…Others have shown that RA patients have a different serum metabolite signature compared to healthy controls [ 12 , 13 , 14 , 15 ]. Study results from a literature review showed that essential amino acids (citric acid, isoleucine, methionine, valine) and non-essential amino acids (threonine, histidine and alanine) were consistently lower in RA patients compared to healthy controls [ 16 ]. Additionally, differences in metabolic profiles have been associated with different stages of disease [ 14 , 15 ] as well as in relation to treatment response [ 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Metabolic Biomarkers in Relation to Methotrexate Response in Early Rheumatoid Arthritis

Gosselt

Muller

Jansen

et al. 2020

JPM

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This study aimed to identify baseline metabolic biomarkers for response to methotrexate (MTX) therapy in rheumatoid arthritis (RA) using an untargeted method. In total, 82 baseline plasma samples (41 insufficient responders and 41 sufficient responders to MTX) were selected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, trial number: ISRCTN26791028) based on patients’ EULAR response at 3 months. Metabolites were assessed using high-performance liquid chromatography-quadrupole time of flight mass spectrometry. Differences in metabolite concentrations between insufficient and sufficient responders were assessed using partial least square regression discriminant analysis (PLS-DA) and Welch’s t-test. The predictive performance of the most significant findings was assessed in a receiver operating characteristic plot with area under the curve (AUC), sensitivity and specificity. Finally, overrepresentation analysis was performed to assess if the best discriminating metabolites were enriched in specific metabolic events. Baseline concentrations of homocystine, taurine, adenosine triphosphate, guanosine diphosphate and uric acid were significantly lower in plasma of insufficient responders versus sufficient responders, while glycolytic intermediates 1,3-/2,3-diphosphoglyceric acid, glycerol-3-phosphate and phosphoenolpyruvate were significantly higher in insufficient responders. Homocystine, glycerol-3-phosphate and 1,3-/2,3-diphosphoglyceric acid were independent predictors and together showed a high AUC of 0.81 (95% CI: 0.72–0.91) for the prediction of insufficient response, with corresponding sensitivity of 0.78 and specificity of 0.76. The Warburg effect, glycolysis and amino acid metabolism were identified as underlying metabolic events playing a role in clinical response to MTX in early RA. New metabolites and potential underlying metabolic events correlating with MTX response in early RA were identified, which warrant validation in external cohorts.

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“…Regarding RA, metabolomics can help elucidate the disease pathogenesis that has not been fully understood until now [ 171 ]. Metabolomic profiling has been employed to understand and predict the outcome of therapy in RA, in cases of treatment with rituximab [ 172 ], methotrexate [ 173 ], tocilizumab, and their combination [ 174 ].…”

Section: Immunometabolism As a Key Factor In Elucidating Signalingmentioning

confidence: 99%

Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches

Aghakhani

Zerrouk

Niarakis

2020

Cancers

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Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modeling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.

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Metabolomics in the development and progression of rheumatoid arthritis: A systematic review

Cited by 45 publications

References 53 publications

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

Identification of Metabolic Biomarkers in Relation to Methotrexate Response in Early Rheumatoid Arthritis

Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches

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