Inhibition of 6-phosphofructo-2-kinase suppresses fibroblast-like synoviocytes-mediated synovial inflammation and joint destruction in rheumatoid arthritis
Inhibition of 6-phosphofructo-2-kinase suppresses fibroblast-like synoviocytes-mediated synovial inflammation and joint destruction in rheumatoid arthritis
复制标题
抑制 6-磷酸果糖-2-激酶可抑制类风湿关节炎中成纤维细胞样滑膜细胞介导的滑膜炎症和关节破坏
DOI：
10.1111/bph.13762
复制
发表时间：
2017
影响因子：
7.3
通讯作者：
Xu Hanshi
中科院分区：
文献类型：
--
作者：
Zou Yaoyao;Zeng Shan;Huang Mingcheng;Qiu Qian;Xiao Youjun;Shi Maohua;Zhan Zhongping;Liang Liuqin;Yang Xiuyan;Xu Hanshi
背景和目的糖酵解代谢异常会导致类风湿性关节炎 (RA) 的关节炎症。本研究的目的是调查 6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶 3 (PFKFB3)（一种控制糖酵解速率的双功能酶）在调节 RA 中成纤维细胞样滑膜细胞 (FLS) 介导的滑膜炎症和侵袭性中的作用。实验方法使用 PFKFB3、PFK15 和 siRNA 的特异性抑制剂评估 PFKFB3 的作用。通过蛋白质印迹或免疫荧光染色测量蛋白质表达。通过实时定量PCR测定细胞因子的表达。使用博伊登室测定法测量迁移和入侵。使用胶原诱导性关节炎 (CIA) 小鼠模型来评估 PFK15 的体内效果。 主要结果 与骨关节炎患者相比，RA 患者的滑膜组织和 FLS 中 PFKFB3 表达增加。 PFKFB3 抑制降低了 IL-8、IL-6、CCL-2 和 CXCL-10 的表达以及 RA FLS 的增殖、迁移和侵袭。 PFK15 抑制 RA FLS 中 TNF-α 诱导的 NF-κB 和 p38、JNK 和 ERK MAPK 信号的激活。 PFK15 治疗还抑制葡萄糖摄取和乳酸分泌。乳酸逆转了 PFK15 或 PFKFB3 siRNA 对细胞因子表达和 RA FLS 迁移的抑制作用。乳酸还参与 PFKFB3 介导的 NF-κB 和 MAPK 激活。腹腔注射 PFK15 可以减轻 CIA 小鼠的关节炎症。 结论和意义 PFKFB3 表达升高可能导致 RA FLS 的滑膜炎症和攻击行为，这表明了一种靶向 PFKFB3 来预防 RA 滑膜炎症和关节破坏的新策略。
Background and PurposeAbnormal glycolytic metabolism contributes to joint inflammation in rheumatoid arthritis (RA). The aims of this study were to investigate the role of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (PFKFB3), a bifunctional enzyme that controls the glycolytic rate, in regulating fibroblast‐like synoviocyte (FLS)‐mediated synovial inflammation and invasiveness in RA.Experimental ApproachA specific inhibitor of PFKFB3, PFK15, and siRNA were used to evaluate the role of PFKFB3. Protein expression was measured by Western blotting or immunofluorescence staining. The expression of cytokines was determined by quantitative real‐time PCR. Migration and invasion were measured using a Boyden chamber assay. A mouse model of collagen‐induced arthritis (CIA) was used to evaluate thein vivoeffect of PFK15.Key ResultsPFKFB3 expression was increased in the synovial tissue and FLSs from RA patients compared with osteoarthritis patients. PFKFB3 inhibition decreased the expression of IL‐8, IL‐6, CCL‐2 and CXCL‐10 and the proliferation, migration and invasion of RA FLSs. PFK15 suppressed TNF‐α‐induced activation of NF‐κB and p38, JNK and ERK MAPK signals in RA FLSs. PFK15 treatment also suppressed glucose uptake and lactate secretion. Lactate reversed the inhibitory effect of PFK15 or PFKFB3 siRNA on cytokine expression and migration of RA FLSs. Lactate was also involved in PFKFB3‐mediated activation of NF‐κB and MAPKs. Intraperitoneal injection of PFK15 in mice with CIA attenuated joint inflammation.Conclusion and ImplicationsElevated PFKFB3 expression might contribute to synovial inflammation and aggressive behaviours of RA FLSs, suggesting a novel strategy of targeting PFKFB3 to prevent synovial inflammation and joint destruction in RA.