Can Metabolic Pathways Be Therapeutic Targets in Rheumatoid Arthritis?

Abstract

The metabolic rewiring of tumor cells and immune cells has been viewed as a promising source of novel drug targets. Many of the molecular pathways implicated in rheumatoid arthritis (RA) directly modify synovium metabolism and transform the resident cells, such as the fibroblast-like synoviocytes (FLS), and the synovial tissue macrophages (STM), toward an overproduction of enzymes, which degrade cartilage and bone, and cytokines, which promote immune cell infiltration. Recent studies have shown metabolic changes in stromal and immune cells from RA patients. Metabolic disruption in the synovium provide the opportunity to use in vivo metabolism-based imaging techniques for patient stratification and to monitor treatment response. In addition, these metabolic changes may be therapeutically targetable. Thus, resetting metabolism of the synovial membrane offers additional opportunities for disease modulation and restoration of homeostasis in RA. In fact, rheumatologists already use the antimetabolite methotrexate, a chemotherapy agent, for the treatment of patients with inflammatory arthritis. Metabolic targets that do not compromise systemic homeostasis or corresponding metabolic functions in normal cells could increase the drug armamentarium in rheumatic diseases for combination therapy independent of systemic immunosuppression. This article summarizes what is known about metabolism in synovial tissue cells and highlights chemotherapies that target metabolism as potential future therapeutic strategies for RA.

Keywords: clinical trials; fibroblasts; macrophages; metabolism; synovium.

Figure 1

Positron emission tomography (PET) methods that provide information on the underlying biochemical processes. PET imaging not only can improve clinical diagnostics but also potentially predict treatment effects. ¹⁸F-FDG, 2-deoxy-2-(fluorine-18)fluoro-D-glucose, provides information on glycolysis and glucose uptake; ¹¹C-DASA23, a class of N, N-diarylsulfonamides, is able to measure PKM2 uptake; ¹⁸F-Gln, ¹⁸F-(2S,4R)4-fluoroglutamine, allows for the monitoring of glutamine metabolism. ¹¹C-Met, ¹¹C-methionine; ¹⁸F-FET, O-(2-[¹⁸F]fluoroethyl)-L-tyrosine; ¹⁸F-FAMT, L-3-(18F)-Fluoro-α-methyl tyrosine; radiolabeled methionine and tyrosine can provide data on amino acid uptake and protein synthesis. Finally, ¹¹C-acetate is converted to acetyl-CoA and used in mitochondria in TCA cycle or incorporated into cell membranes. MCT4, monocarboxylate transporter 4; GLUT1, glucose transporter 1; MCT1, monocarboxylate transporter 1; R-5-P, ribose-5-phosphate; PGD, phosphogluconate dehydrogenase; 6-PG, 6-phosphogluconate; G6PD, glucose-6-phosphate-dehydrogenase; HK, hexokinase; PFK1, phosphofructokinase 1; F2,6BP, fructose-2,6-bisphosphate; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; TS, thymidylate synthase; THF, tetrahydrofolate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; CK, choline kinase; PKM2, pyruvate kinase muscle isozyme M2; LDHα, lactate dehydrogenase A; CA, carbonic anhydrase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; PDK1, pyruvate dehydrogenase kinase 1; IDH, isocitrate dehydrogenase; α-KGDH, alpha-ketoglutarate dehydrogenase; GLS, glutaminase.

Figure 2

Anticancer agents targeting various metabolic pathways that are upregulated in activated cells. Since synovial tissue cells share many similar metabolic changes, these very same antimetabolites may also have potential uses in RA. MCT4, monocarboxylate transporter 4; GLUT1, glucose transporter 1; MCT1, monocarboxylate transporter 1; R-5-P, ribose-5-phosphate; PGD, phosphogluconate dehydrogenase; 6-PG, 6-phosphogluconate; G6PD, glucose-6-phosphate-dehydrogenase; HK, hexokinase; PFK1, phosphofructokinase 1; F2,6BP, fructose-2,6-bisphosphate; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; TS, thymidylate synthase; THF, tetrahydrofolate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; CK, choline kinase; PKM2, pyruvate kinase muscle isozyme M2; LDHα, lactate dehydrogenase A; CA, carbonic anhydrase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; PDK1, pyruvate dehydrogenase kinase 1; IDH, isocitrate dehydrogenase; α-KGDH, alpha-ketoglutarate dehydrogenase; GLS, glutaminase.