Fibroblast-Like Synoviocytes Glucose Metabolism as a Therapeutic Target in Rheumatoid Arthritis

Patricia Gnieslaw De Oliveira,Elsa Sanchez-Lopez,Shigeki Miyamoto,Mirian Farinon,Monica Guma

doi:10.3389/fimmu.2019.01743

Patricia Gnieslaw De Oliveira, Elsa Sanchez-Lopez + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2019.01743

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Abstract

Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption that may be therapeutically targetable. Among them, glucose metabolism and glycolytic intermediaries seem to have an important role in fibroblast-like synoviocytes (FLS) phenotype and might contribute to early stage disease pathogenesis. RA FLS are transformed from quiescent to aggressive and metabolically active cells and several works have shown that glucose metabolism is increased in activated FLS. Glycolytic inhibitors reduce not only FLS aggressive phenotype in vitro but also decrease bone and cartilage damage in several murine models of arthritis. Essential glycolytic enzymes, including hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) enzymes, have important roles in FLS behavior. Of interest, HK2 is an inducible enzyme present only in the inflamed rheumatic tissues compared to osteoarthritis synovium. It is a contributor to glucose metabolism that could be selectively targeted without compromising systemic homeostasis as a novel approach for combination therapy independent of systemic immunosuppression. More information about metabolic targets that do not compromise global glucose metabolism in normal cells is needed.

Highlights

Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption that may be therapeutically targetable
RA fibroblast-like synoviocytes (FLS) are transformed from quiescent to aggressive and metabolically active cells and several works have shown that glucose metabolism is increased in activated FLS
The most important carbohydrate is glucose, which is first transported into the cell through glucose transporter 1 (GLUT1), broken down via glycolysis by sequential metabolic enzymes [including hexokinase (HK), aldolase, phosphoglycerate kinase (PGK1), and pyruvate kinase] to generate pyruvate, and afterwards will either enter into the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to generate ATP, or will be converted to lactate via lactate dehydrogenase (LDH)

Summary

Glucose Metabolism in FLS

An increasing number of studies have shown that FLS activation and the subsequent joint damage are associated with an altered metabolism which may be therapeutically targetable. The metabolism of all four major classes of macromolecules (carbohydrates, proteins, lipids, and nucleic acids) will change after cell activation. Prior work—ours and others—has shown that glucose metabolism is increased in activated FLS, and glycolytic inhibition reduces FLS aggressive phenotype in vitro and decreases bone and cartilage damage in several murine models of arthritis [(11–13); Table 1]. These works have suggested potential metabolic targets to reprogram metabolic disruptions and complement current therapies [11,12,13].

GLUCOSE METABOLISM ACTIVATION IN THE RA FLS

Lactate Succinate

Increased levels of lactate induced FLS invasiveness

FLS GLUCOSE METABOLISM AND CHRONIC ACTIVATION IN RA

GLUCOSE METABOLISM TARGETS IN RA FLS

CONCLUSION