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

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.

Keywords: fibroblast-like synoviocytes; glucose metabolism; glycolytic inhibitors; hexokinase-2; rheumatoid arthritis.

Figure 1

Fibroblasts-like synoviocytes (FLS) glucose metabolism and chronic activation in RA. (A) Chronic glucose metabolic changes induced by hypoxia and inflammatory mediators in FLS will activate many signaling pathways, including HIF, MAPK, PI3K/Akt, and JAK/STAT pathways, which also increases the expression of key glucose metabolism related genes such as GLUT1, HK2, or LDH. Intermediate glucose metabolites including pyruvate, lactate, succinate, a-ketoglutarate, fumarate, and acetyl-coenzyme will create a chronic and sustained FLS activation, either by being secreted extracellularly and triggering profound effects on the biology of other cells, or by inducing a new epigenetic landscape that results in a stable FLS activation that is maintained even without continuous stimulation. (B) Hypoxia, growth factors, and cytokines in arthritis synovium stimulate Akt phosphorylation, which will up-regulate HK2 expression and HK2 phosphorylation. The phosphorylation of HK2 by Akt is accompanied by an increased binding of the enzyme to mitochondrial outer membrane voltage-dependent anion channel (VDAC). Binding to VDAC enhances the affinity of hexokinases. Therefore, HK2 mitochondrial binding might promote glucose metabolism and FLS invasive phenotype. Mitochondrial HK2 might also inhibit apoptosis. Thus, mitochondrial association of HK2 might promote resistance to growth, invasion, and apoptosis of RA FLS, which contribute to joint destruction in RA. Selective HK2 mitochondrial dissociation might be an attractive potential selective target for arthritis therapy and safer than global glycolysis inhibition. HK2, hexokinase 2; G6PD, glucose 6 phosphate dehydrogenase; PKM2, pyruvate kinase muscle isozyme M2; PFK, phosphofructokinase; PFKB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; F1,6BP, Fructose 1,6-bisphosphate; F2,6FB, Fructose 2,6-bisphosphate; VDAC: voltage-dependent anion channel.