ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2137

Critical Role of Fibroblast-like Synoviocytes Glycolytic Metabolism in Rheumatoid Arthritis

Ricard Garcia-Carbonell1, Ajit Divakaruni1, Alessia Lodi2, Ildefonso Vicente-Suarez3, Hilde Cheroutre4, Gerry Boss1, Arindam Saha1, Stefano Tiziani5, Anne Murphy6, Gary S. Firestein7 and Monica Guma6, 1University of California, San Diego, La Jolla, CA, 2nutritional Sciences, University of Texas at Austin, Austin, TX, 3LIAI, La Jolla, CA, 4Autoimmune Research, LIAI, La Jolla, CA, 5Nutritional Sciences, University of Texas at Austin, Austin, TX, 6Pharmacology, University of California, San Diego, La Jolla, CA, 7Division of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: , ,

Session Information

Date: Monday, November 9, 2015

Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis II

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

 

Background/Purpose: Glucose metabolism is altered not only in tumor cell growth but also in immune cells on activation. However, little is known about glucose metabolism in fibroblast-like synoviocytes (FLS). We recently showed that a glycolysis inhibitor suppressed the aggressive behavior of cultured RA FLS, including proliferation, cytokine secretion and cell migration. Here, we further evaluated changes in glucose metabolism in both RA synovium and RA FLS and its role in inflammation and joint damage.

Methods: The glucose metabolism profile of synovium was determined by 1H-MRS. Analysis of FLS oxygen consumption/extracellular acidification was determined by Seahorse technology. Effect of inflammatory mediators on the glycolytic rate in FLS was determined by Seahorse after LPS and PDGF stimulation. Glucose metabolism related gene expression was determined by qPCR. The increase of glycolysis in a murine model was determined using IRDye®800CW 2-DG, a fluorescent optical imaging agent that assesses glucose uptake, and by FACS. For arthritis experiments, the glycolysis inhibitor bromopyruvate (BrPa; 5mg/kg) was injected daily i.p. at the peak of arthritis in two murine models, passive K/BxN model (from day 5) and collagen induced arthritis (from day 35).

Results: Compared to osteoarthritis (OA), RA FLS had a higher baseline glycolytic rate, a decreased mitochondrial respiration and increased extracellular acidification after LPS stimulation. Intracellular lactate was also higher in RA synovium and several metabolites related to glucose metabolism correlated with lactate levels, suggesting higher glucose metabolism in RA synovium samples. Glucose transporter 1 (GLUT1) expression correlated with FLS baseline functions and her expression increased after LPS and PDGF stimulation. In a mouse model of inflammatory arthritis, we observed an increase of glucose uptake in arthritic joints and an increase of glucose uptake and glycolytic gene expression in the CD45-PDPN+ stromal cell compartment. Glycolytic inhibition by BrPa administered in vivo significantly decreased arthritis severity in both animal models.

Conclusion: Targeting metabolic dysfunction offers a novel approach of understanding the mechanisms of disease and potential new treatments. Glycolytic inhibition may directly modulate synoviocyte-mediated inflammatory functions and could be an effective treatment strategy for arthritis.

Disclosure: R. Garcia-Carbonell, None; A. Divakaruni, None; A. Lodi, None; I. Vicente-Suarez, None; H. Cheroutre, None; G. Boss, None; A. Saha, None; S. Tiziani, None; A. Murphy, None; G. S. Firestein, None; M. Guma, None.

To cite this abstract in AMA style:

Garcia-Carbonell R, Divakaruni A, Lodi A, Vicente-Suarez I, Cheroutre H, Boss G, Saha A, Tiziani S, Murphy A, Firestein GS, Guma M. Critical Role of Fibroblast-like Synoviocytes Glycolytic Metabolism in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/critical-role-of-fibroblast-like-synoviocytes-glycolytic-metabolism-in-rheumatoid-arthritis/. Accessed April 13, 2021.

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