Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis

Abstract

Introduction Abnormal glycolytic metabolism contributes to joint inflammation and destruction in rheumatoid arthritis (RA). We examine the expression and function of hexokinases in RA and evaluate the potential of their specific inhibitor for clinical treatment. Methods Detection of HKs was assessed in synovial tissue by immunohistology and Western blot. SiRNA and a specific hexokinases inhibitor, lonidamine (LND), were used to evaluate the role of hexokinase-I/II (HK-I/II). Pro-inflammatory and glycolysis factors, cell viability, and apoptosis were assessed by ELISA, RT-qPCR, MTS, and flow cytometry. The clinical effects of LND on type II collagen-induced arthritis (CIA) in DBA-/1 mouse model was evaluated by scoring their clinical responses, synovitis, and cartilage destructions, and ELISA was employed to analyze the concentrations of antibody in the serum of CIA model. Results HK-I/II expression and their activities increased in the synovium of RA compared with osteoarthritis (OA). Silencing HK-I/II (siHK-I/II) or LND treatment decreased the production of pro-inflammatory factors, such as IL-6, IL-8, CXCL9, CXCL10, and CXCL11, and cell viability, but induced cell apoptosis of RASFs. The expression of TNF-α and IL-1β of macrophage in response to LPS stimulation were depressed as well after treatment with siHK-I/II or LND. Furthermore, leucocyte infiltration co-cultured with RASFs was also suppressed after inhibiting the expression or activity of HK-I/II. These anti-inflammatory effects overlapped with their anti-glycolytic activities. Treatment with LND in mice with CIA decreased the production of antibodies against IgG1, IgG2a, and IgG2b and consequently attenuated joint inflammation and destruction. Conclusions HK-I/II contribute to shape the inflammatory phenotype of RASFs and macrophages. LND may be a potential drug in treating patients with RA. Electronic supplementary material The online version of this article (10.1186/s13075-019-1865-3) contains supplementary material, which is available to authorized users.

Exercise Exacerbates the Transcriptional Profile of Hypoxia, Oxidative Stress and Inflammation in Rats with Adjuvant-Induced Arthritis

“…Abnormal glucose metabolism was observed in the synovial fluid and synovium of RA, which is evidenced by increased glycolytic enzyme activity [40]. A recent study proposes the inhibition of hexokinases as a potential therapeutic strategy in the treatment of patients with RA [41]. According to this, the glucokinase (Gck) and the hexokinase 1 (Hk1) were up-regulated by PE in our study.…”

IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection

“…Hence, inhibition of the first and middle steps of glycolysis results in reduced cytokine production by bona fide Th1 cells during infection and had no impact on Tr1 cells, suggesting that IL-27 signalling regulates glycolysis specifically in Th1 cells. Blocking glycolysis can reduce disease severity in inflammatory environments such as those found in arthritis [ 74 , 75 ], cancer [ 76 ], autoimmunity [ 77 ] and infections [ 48 ]. Our findings presented here highlight the importance of understanding the metabolic changes that occur during inflammation and how these pathways could potentially be targeted to restore functionality to tissues affected by inflammatory-mediated damage.…”

Glucose transporter 1 in rheumatoid arthritis and autoimmunity

“…This experiment proved sensitivity of disease‐relevant immune cell types to broad inhibition of glycolysis. Recently, treatment with lonidamine (Figure ), a hexokinase inhibitor, also slightly improved arthritis in the collagen‐induced arthritis model and significantly lowered the development of anti‐collagenII antibodies (Song et al, ).…”