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

Abstract

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.

Neutrophils in Extravascular Body Fluids: Cytological-Energy Analysis Enables Rapid, Reliable and Inexpensive Detection of Purulent Inflammation and Tissue Damage

“…However, hyperglycemia can lead to increased concentrations of glucose in EBF and can mask glucose consumption during inflammation in the affected body compartment [15,16]. Furthermore, the generally accepted scheme of glucose metabolism indicates that the concentration of lactate in EBF is not influenced exclusively by the extent of anaerobic metabolism in EBF but also by the supply of the energy substrate, i.e., glucose (Figure 1) [17][18][19]. Neutrophils are the principal cells of innate immunity.…”

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

“…This switch in cell metabolism, not related to oxygen availability, is the so-called Warburg effect or aerobic glycolysis [ 104 ]. In this sense, recent findings point out glycolysis rate-limiting enzymes as novel potential regulators of RA pathogenesis [ 105 ]. In fact, it has been shown that the expression of the first rate-limiting enzyme of glycolysis, hexokinase 2 (HK2), is elevated in the RA synovial tissue, as well as that its overexpression in the synovial lining of a preclinical model promotes hypertrophy of healthy synovium and an aggressive synovial phenotype.…”

“…Interestingly, enhanced metabolism is needed to contribute to the abnormal synovial hyperplasia associated with local infiltration of various type of immune and inflammatory cells that define the synovial pannus . In this sense, a body of recent research indicates glycolysis rate-limiting enzymes as novel potential regulators of RA pathogenesis [ 105 ]. In fact, regulation lactate metabolism imbalance could allow revolutionary pharmacological approaches to restore mitochondrial function in RA [ 302 ].…”

Noncoding RNAs in the Glycolysis of Ovarian Cancer

“…Glycolysis is a complex process that starts with glucose catalyzation by various non-rate limiting and rate-limiting enzymes to form lactate ( Ganapathy-Kanniappan 2018 ; Fan et al, 2019 ). The classical glycolysis involves three rate-limiting enzymes, HK, PFK, and PK, mediating different processes and playing essential roles in glucose metabolism ( Shakespear et al, 2018 ; Yellen 2018 ), HK has four isoforms, HKI, HKII, HKIII, and HKIV, catalyzing glucose to glucose-6-phosphate (G6P) ( Zuo et al, 2021 ). HKI and HKII present high affinity for mitochondria, and HK1 expression is present in most mammalian tissues ( Zhong and Zhou 2017 ; Garcia et al, 2019 ).…”

“…Fructose 2, 6-bisphosphate (F26BP) can diminish the inhibition of ATP and increase glucose uptake by interacting with PFK1( Kalezic et al, 2021 ; Zuo et al, 2021 ). The substrate can abnormally inhibit PFK, and ATP has a dual effect on PFK (PK is an evolutionarily conserved metabolic enzyme that catalyzes pyruvate production from phosphoenolpyruvate) ( Shen et al, 2020 ; Zhao et al, 2020 ).…”