Abstract
IntroductionAbnormal 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.MethodsDetection 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.ResultsHK-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.ConclusionsHK-I/II contribute to shape the inflammatory phenotype of RASFs and macrophages. LND may be a potential drug in treating patients with RA.
Highlights
Abnormal glycolytic metabolism contributes to joint inflammation and destruction in rheumatoid arthritis (RA)
HK-I and HK-II are crucial mediators for glycolysis and survival for rheumatoid arthritis synovial fibroblasts (RASFs) As HK I and HK II are two main factors overexpressing in RASFs, we examined the effects of HK-I and HK-II on glycolysis after silencing HK-I, HK-II, or both of them
LND suppresses the production of inflammatory factors in both RASFs and THP-1 cells we evaluated the anti-inflammatory effect of LND
Summary
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. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial proliferation and leukocyte extravasation leading to joint destruction [1]. An abnormal glucose metabolism was observed in the synovial. Blocking glycolysis might be beneficial for RA and the exploration of novel hub linking glycolytic metabolism and inflammation might be promising in RA treatment. Glycolytic metabolism is modulated by membrane glucose transporters (GLUTs), hexokinases (HKs) activity, and fructose 2,6-bisphosphate levels [8,9,10]. We further identified that HK-I and HK-II were mainly expressed in the synovial tissues of RA patients when compared with those of OA patients, further supporting their likely involvement in RA
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