Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

Rheumatoid arthritis (RA) is a classic autoimmune disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. The specific pathogenesis of RA, a chronic inflammatory disease, remains unclear. However, both key glycolysis rate-limiting enzymes, hexokinase-II (HK-II), phosphofructokinase-1 (PFK-1), and pyruvate kinase M2 (PKM2), as well as indirect rate-limiting enzymes, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), are thought to participate in the pathogenesis of RA. In here, we review the latest literature on the pathogenesis of RA, introduce the pathophysiological characteristics of HK-II, PFK-1/PFKFB3, and PKM2 and their expression characteristics in this autoimmune disease, and systematically assess the association between the glycolytic rate-limiting enzymes and RA from a molecular level. Moreover, we highlight HK-II, PFK-1/PFKFB3, and PKM2 as potential targets for the clinical treatment of RA. There is great potential to develop new anti-rheumatic therapies through safe inhibition or overexpression of glycolysis rate-limiting enzymes.

Plasma Interleukin-21 Levels and Genetic Variants Are Associated With Susceptibility to Rheumatoid Arthritis

Background Rheumatoid Arthritis (RA ) is a chronic inflammatory condition characterised by the development of autoantibodies and an elevated spectrum of proinflammatory cytokines. Previous reports highlighted a relationship between IL-21and pathogenesis of RA. Although elevated IL-21 levels have been reported in RA patients, the association of common IL-21 genetic variants with a predisposition to RA development in the Chinese population is lacking. Materials and methods Five hundred and fourteen Chinese subjects (healthy controls: 303 and rheumatoid arthritis patients: 211) were enrolled in the study. Clinical data of patients were collected from medical records, and patients were treated as per the guidelines. IL-21 level in plasma of RA patients and healthy subjects was measured by ELISA. Results The plasma level of IL-21 was significantly higher in subjects with rheumatoid arthritis relative to healthy controls. A positive correlation was observed between IL-21 level and DAS28 score, indicating the association of the cytokine with the worsening of the disease. The prevalence of AA genotype (rs2055979) was significantly higher in RA subects compared to controls. Furthermore, elevated plasma IL-21 was observed in the rs2055979-AA genotype compared to CC type. Conclusion IL-21 plays a key function in rheumatoid arthritis pathogenesis. IL-21 rs2055979 polymorphism is associated with IL-21 plasma levels and is predisposed to RA development in Chinese population.

Synovial biopsies

Synovial tissue is the primary tissue inflamed in rheumatoid arthritis. Initial studies of synovial biopsies were obtained during arthroplasty or using a needle to biopsy the joint percutaneously. Recently, small needle arthroscopy or ultrasonography guided techniques have become more widely available to visualize and reliably obtain synovial biopsies. These techniques have allowed significant progress in the study of rheumatoid arthritis pathogenesis, even at the earliest stages of disease. Currently, research efforts are underway to use synovial biopsies to identify patients and to discover biomarkers that will enable clinicians to predict the course of the disease and perhaps to identify more appropriately the correct therapy for patients with rheumatoid arthritis. In this chapter, we describe the advances in synovial tissue biopsy research and how it has improved our knowledge of rheumatoid arthritis pathogenesis, informed our understanding of possible biomarkers for diagnosis and stratification, and potentially may aid in the prediction of disease outcome and response to treatment.

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA.