Increased hexokinase-2 as a novel biomarker for the diagnosis and correlating with disease severity in rheumatoid arthritis

Abstract

Abnormal glucose metabolism brings out joint inflammation and destruction in rheumatoid arthritis (RA). The aim of this study was to evaluate the potential of circulating hexokinase-2 (HK2) in peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients. PBMCs were obtained from patients with RA or osteoarthritis (OA) and healthy controls (HCs). The expression of HK2 was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), Calprotectin, rheumatoid factor (RF), anti-cyclic citrullinated peptides (anti-CCP) antibody level and 28-joint Disease Activity Score (DAS28), Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) were measured. Spearman ' s analysis was performed to determine the association between the level of HK2 and clinical characteristics. A receiver operating characteristic (ROC) curve was employed to evaluate the diagnostic value of HK2 in PBMCs. Logistic regression was used to identify risk factors. Sixty-five RA patients, 35 OA patients, and 40 HCs were included in the study. HK2 was upregulated in RA and OA patients compared with that in HCs ( P < .05). The area under the ROC of HK2 for diagnosing RA and OA was 0.808 and 0.640, respectively. In addition, HK2 levels were increased in active RA compared with those in remittent RA ( P = .03). Furthermore, HK2 correlated positively with the DAS28-ESR ( P < .001), CDAI ( P = .02) and SDAI scores ( P = .02). Moreover, HK2 was independently associated with an increased risk of disease activity (DAS28-ESR>3.2, P = .02; CDAI score>10, P = .03; SDAI score>11, P = .04). Additionally, HK2 positivity was more frequently detected in patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) than in those not treated with bDMARDs. HK2 levels in PBMCs can be considered an ideal biomarker for diagnosing RA and involved in disease activity in RA. Dysregulation of HK2 may participate in the molecular mechanism of RA and could be an attractive selective metabolic target for RA treatment.

HK2: a potential regulator of osteoarthritis via glycolytic and non-glycolytic pathways

“…Interestingly, another hexokinase isoform HKI was also increased in the treated cells [55]. A present study with a focus on HK2 validated that the expression of HK2 was increased in peripheral blood mononuclear cells (PBMCs) compared with that in HCs examined by real-time PCR in an RA and OA cohort [56]. These findings highlight that HK2 may be involved in the pathogenesis of OA.…”

Intra-Articular Lactate Dehydrogenase A Inhibitor Oxamate Reduces Experimental Osteoarthritis and Nociception in Rats via Possible Alteration of Glycolysis-Related Protein Expression in Cartilage Tissue

“…Additionally, hexokinase-II has been shown to reprogram tumor cell metabolism to aerobic glycolysis [ 36 ]. A previous study revealed that hexokinase-II expression in peripheral blood mononuclear cells is higher in patients with OA than in healthy individuals [ 37 ]. TGF-β1 upregulates hexokinase-II protein expression in OA chondrocytes, induces aerobic glycolysis, increases glucose consumption and lactate synthesis, and decreases ATP synthesis simultaneously [ 38 ].…”

Providing a Helping Hand: Metabolic Regulation of T Follicular Helper Cells and Their Association With Disease

“…Moreover, Tfh from K/BxN mice that develop spontaneous rheumatoid arthritis exhibit a heightened glycolytic demand and inhibition of glycolysis impairs their function reducing disease severity ( 102 ). Further support of the requirement of glycolysis for proper Tfh functioning is through reports of human rheumatoid arthritis patients expressing higher levels of hexokinase 2 in peripheral blood mononuclear cells in comparison to their healthy counterparts ( 119 ). Moreover, in vitro Tfh differentiation is diminished when cultured in low glucose ( 110 ).…”