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Inhibition of 6‐phosphofructo‐2‐kinase suppresses fibroblast‐like synoviocytes‐mediated synovial inflammation and joint destruction in rheumatoid arthritis
Author(s) -
Zou Yaoyao,
Zeng Shan,
Huang Mingcheng,
Qiu Qian,
Xiao Youjun,
Shi Maohua,
Zhan Zhongping,
Liang Liuqin,
Yang Xiuyan,
Xu Hanshi
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13762
Subject(s) - inflammation , arthritis , mapk/erk pathway , synovial joint , rheumatoid arthritis , p38 mitogen activated protein kinases , kinase , proinflammatory cytokine , tumor necrosis factor alpha , cancer research , chemistry , lipopolysaccharide , cytokine , immunology , medicine , osteoarthritis , pathology , biochemistry , alternative medicine , articular cartilage
Background and Purpose Abnormal 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 Approach A 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 the in vivo effect of PFK15. Key Results PFKFB3 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 Implications Elevated 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.