title: PI3 kinase/Akt/HIF-1α pathway is associated with hypoxia-induced epithelial-mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis.
abstract: Migration and invasion of fibroblast-like synoviocytes (FLSs) are critical in the pathogenesis of rheumatoid arthritis (RA). Hypoxic conditions are present in RA joints, and hypoxia has been extensively studied in angiogenesis and inflammation. However, its effect on the migration and invasion of RA-FLSs remains unknown. In this study, we observed that RA-FLSs exposed to hypoxic conditions experienced epithelial-mesenchymal transition (EMT), with increased cell migration and invasion. We demonstrated that hypoxia-induced EMT was accompanied by increased hypoxia-inducible factor (HIF)-1α expression and activation of Akt. After knockdown or inhibition of HIF-1α in hypoxia by small interfering RNA or genistein (Gen) treatment, the EMT transformation and invasion ability of FLSs were regained. HIF-1α could be blocked by phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, indicating that HIF-1α activation was regulated by the PI3K/Akt pathway. Administration of LY294002 (20 mg/kg, intra-peritoneally) twice weekly and Gen (25 mg/kg, by gavage) daily for 3 weeks from day 20 after primary immunization in a collagen-induced arthritis rat model, markedly alleviated the clinical signs, radiology progression, synovial hyperplasia, and inflammatory cells infiltration of joints. Thus, results of this study suggest that activation of the PI3K/Akt/HIF-1α pathway plays a pivotal role in mediating hypoxia-induced EMT transformation and invasion of RA-FLSs under hypoxia.
authors.affiliation: Department of Rheumatology, Clinical Medical College, Yangzhou University, Yangzhou 225001, Jiangsu, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Qian
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Shi-Yu
authors.initials: SY
authors.lastname: Guo
authors.forename: Masataka
authors.initials: M
authors.lastname: Sunagawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hisamitsu
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Liu
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D002465:Cell Movement; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D019833:Genistein / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007719:Knee Joint / Q000473:pathology; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013582:Synovial Fluid / Q000201:enzymology / Q000378:metabolism
chemical_list: D002867:Chromones; D019833:Genistein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C497442:HIF1A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one