Defective glucose and lipid metabolism in rheumatoid arthritis is determined by chronic inflammation in metabolic tissues

Rosa, I. Arias de la; Contreras, A. Escudero; Rodríguez‐Cuenca, Sergio; Ruiz-Ponce, M.; Jiménez‐Gómez, Yolanda; Ruiz-Limón, P.; Pérez-Sánchez, C.; Ábalos-Aguilera, M. C.; Cecchi, Irene; Ortega, R.; Calvo, J.; Guzmán‐Ruiz, Rocío; Malagón, Marı́a M.; Collantes-Estévez, Eduardo; Vidal-Puig, António; López-Pedrera, C.; Barbarroja, Nuria

doi:10.1111/joim.12743

Cited by 40 publications

(34 citation statements)

References 44 publications

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“…The current synovial dataset was used to show that mRNA levels of key enzymes of the cholesterol biosynthesis pathway are significantly associated with arthritis development in at risk individuals suggesting dysregulated IL-10 production (48). In a collagen-induced arthritis mouse model, the inflammatory profile of arthritic mice was linked to defective lipid metabolism (49). In line with our findings, they showed decreased expression of multiple genes related to lipid metabolism including DGAT2, ADIPOQ and LPL (49).…”

Section: Discussionsupporting

confidence: 68%

Synovial Gene Signatures Associated with the Development of Rheumatoid Arthritis in At Risk Individuals: a Prospective Study

Baarsen¹,

Jong²,

Mj³

et al. 2021

Preprint

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Background: Previous work has shown subtle infiltration of synovial T cells in the absence of overt synovial inflammation in individuals at risk of developing rheumatoid arthritis (RA). Objective: To study the molecular changes in synovium preceding arthritis development in at risk individuals. Materials and methods: We included sixty-seven individuals with arthralgia who were IgM rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positive and without any evidence of arthritis. All individuals underwent mini-arthroscopic synovial tissue sampling of a knee joint at baseline and were followed prospectively. An explorative genome-wide transcriptional profiling study was performed on synovial tissue using Agilent arrays (discovery cohort). Survival analysis was used to identify transcripts associated with arthritis after follow up. Expression levels of differentially expressed genes were validated using quantitative real-time PCR (qPCR). Immunohistochemistry was used to study gene candidates at the protein level in situ. Results: In the discovery cohort, 6 of the 13 at risk individuals developed RA after a median follow-up time of 20 months (IQR 2 – 44; pre-RA). The 7 individuals who did not develop RA had a median follow-up time of 85 months (IQR 69 – 86). Using a False Discovery Rate of <5% we found increased expression of 3,151 transcripts correlating with a higher risk of arthritis development, whereas increased expression of 2,437 transcripts correlated with a lower risk. Gene set enrichment analysis revealed that synovial biopsies of pre-RA individuals display higher expression of genes involved in several immune response-related pathways compared with biopsies of individuals who did not develop RA. In contrast, lower expression was observed for genes involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism. Two-way hierarchical cluster analysis of 27 genes measured by qPCR classified the synovial biopsies of 61 individuals into two groups, where pre-RA individuals (n=16) showed a preference to cluster together. Synovial tissue from pre-RA individuals were more likely to show podoplanin positive cells and lower lipid staining compared with synovial tissue from individuals who did not develop RA. Conclusion: Molecular changes can be detected in synovial tissues before clinical onset of arthritis. Alterations in the immune response genes and lipid metabolism are associated with development of arthritis.

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Section: Discussionsupporting

confidence: 68%

Synovial Gene Signatures Associated with the Development of Rheumatoid Arthritis in At Risk Individuals: a Prospective Study

Baarsen¹,

Jong²,

Mj³

et al. 2021

Preprint

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“…28 Thus, we recently reported that metabolic disturbances associated with rheumatoid arthritis depend on the degree of inflammation and identified tumor necrosis factor (TNF)-α and interleukin (IL)-6 as the main actors causing insulin resistance in this disorder. 29 In addition, insulin resistance has been strongly related to the DAS28 in rheumatoid arthritis. 30 All in all, complement C3 could be considered as a surrogate biomarker taken into account in the cardiovascular risk and progression of the disease assessments in rheumatoid arthritis and spondyloarthritis.…”

Section: Discussionmentioning

confidence: 99%

Complement component 3 as biomarker of disease activity and cardiometabolic risk factor in rheumatoid arthritis and spondyloarthritis

Rosa

Font

Contreras

et al. 2020

Therapeutic Advances in Chronic Disease

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Objective: To analyze the relationship between complement component 3 (C3) and the prevalence of cardiometabolic risk factors and disease activity in the rheumatic diseases having the highest rates of cardiovascular morbidity and mortality: rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). Methods: This is a cross-sectional study including 200 RA, 80 PsA, 150 axSpA patients and 100 healthy donors. The prevalence of cardiometabolic risk factors [obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, apolipoprotein B/apolipoprotein A (apoB/apoA) and atherogenic risks and hypertension] was analyzed. Serum complement C3 levels, inflammatory markers and disease activity were evaluated. Cluster analysis was performed to identify different phenotypes. Receiver operating characteristic (ROC) curve analysis to assess the accuracy of complement C3 as biomarker of insulin resistance and disease activity was carried out. Results: Levels of complement C3, significantly elevated in RA, axSpA and PsA patients, were associated with the prevalence of cardiometabolic risk factors. Hard clustering analysis identified two distinctive phenotypes of patients depending on the complement C3 levels and insulin sensitivity state. Patients from cluster 1, characterized by high levels of complement C3 displayed increased prevalence of cardiometabolic risk factors and high disease activity. ROC curve analysis showed that non-obesity related complement C3 levels allowed to identify insulin resistant patients. Conclusions: Complement C3 is associated with the concomitant increased prevalence of cardiometabolic risk factors in rheumatoid arthritis and spondyloarthritis. Thus, complement C3 should be considered a useful marker of insulin resistance and disease activity in these rheumatic disorders.

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“…Similarly, genes regulating insulin sensitivity are known to be downregulated in muscle in inflammatory and catabolic states, including a mouse CIA model [ 10 ]. In our study, several genes linked to insulin signalling were downregulated, including Irs1, Slc2a4, Pparα, Ppargc1α and Ppargc1β.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated levels of inflammatory cytokines have been implicated in aberrant phosphatidylinositol-3-kinase/Akt1 (PI3K/Akt1) signalling [ 8 , 9 ], leading to net negative muscle protein balance and altered muscle metabolic flux [ 6 , 7 ]. Similarly, chronic inflammation in RA has been linked to dysregulation of glucose and lipid metabolism in a murine model [ 10 ], but the underlying mechanisms are yet to be identified [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle dysregulation in rheumatoid arthritis: Metabolic and molecular markers in a rodent model and patients

et al. 2020

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Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identify commonality in muscle gene expression between this model and muscle from RA patients. Pain behaviour and locomotor activity were measured in a collagen-induced arthritis (CIA) model of RA (n = 9) and control (n = 9) rats. Energy substrates and metabolites, total alkaline-soluble protein:DNA ratio and mRNA abundance of 46 targeted genes were also determined in Extensor digitorum longus muscle. Expression of targeted mRNAs was quantified in Vastus Lateralis muscle from RA patients (n = 7) and healthy age-matched control volunteers (n = 6). CIA rats exhibited pain behaviour (p<0.01) and reduced activity (p<0.05) compared to controls. Muscle glycogen content was less (p<0.05) and muscle lactate content greater (p<0.01) in CIA rats. The bioinformatics analysis of muscle mRNA abundance differences from the control, predicted the activation of muscle protein metabolism and inhibition of muscle carbohydrate and fatty acid metabolism in CIA rats. Compared to age-matched control volunteers, RA patients exhibited altered muscle mRNA expression of 8 of the transcripts included as targets in the CIA model of RA. In conclusion, muscle energy metabolism and metabolic gene expression were altered in the CIA model, which was partly corroborated by targeted muscle mRNA measurements in RA patients. This research highlights the negative impact of RA on skeletal muscle metabolic homeostasis.

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Defective glucose and lipid metabolism in rheumatoid arthritis is determined by chronic inflammation in metabolic tissues

Cited by 40 publications

References 44 publications

Synovial Gene Signatures Associated with the Development of Rheumatoid Arthritis in At Risk Individuals: a Prospective Study

Synovial Gene Signatures Associated with the Development of Rheumatoid Arthritis in At Risk Individuals: a Prospective Study

Complement component 3 as biomarker of disease activity and cardiometabolic risk factor in rheumatoid arthritis and spondyloarthritis

Skeletal muscle dysregulation in rheumatoid arthritis: Metabolic and molecular markers in a rodent model and patients

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