title: Enhancement of placenta growth factor expression by oncostatin M in human rheumatoid arthritis synovial fibroblasts.
abstract: Oncostatin M (OSM) belongs to IL-6 subfamily and is mostly produced by T lymphocytes. High levels of OSM are detected in the pannus of rheumatoid arthritis (RA) patients and it may arouse the inflammation responses in joints and eventually leads to bone erosion. Placenta growth factor (PLGF) is an angiogenic factor and highly homologous with vascular endothelial growth factor (VEGF). It has been recently reported that PLGF is highly expressed in synovial tissue and enhances the production of proinflammatory cytokines including TNF-α and IL-6. Here, we demonstrated that OSM increased mRNA and protein levels of PLGF in a time- and concentration-dependent manner in RA synovial fibroblasts. Inhibitors of JAK3 and PI3K antagonized OSM-induced production of PLGF. OSM enhanced the phosphorylation of Tyr705-STAT3, Ser727-STAT3, Ser473-Akt, and increased the nuclear translocation of phosphorylated STAT3 time-dependently. Transfection of dominant negative Akt or application of PI3K inhibitorLY294002 significantly inhibited p-Tyr705-STAT3, p-Ser727-STAT3, and PLGF expression, indicating that Akt is involved in JAK3/STAT3/PLGF signaling cascade. To further examine whether STAT3 binds to the promoter region of PLGF, Chip assay was used and it was found that OSM could bind with PLGF promoter, which was inhibited by JAK3 and PI3K inhibitors. Accumulation of PLGF in the pannus may contribute to the inflammation, angiogenesis and joints destruction in RA patients. These findings demonstrated the important role of OSM in the pathology network of RA and provided novel therapeutic drug targets for RA treatment.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Huang-Ju
authors.initials: HJ
authors.lastname: Tu
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Lin
authors.forename: Yung-Cheng
authors.initials: YC
authors.lastname: Chiu
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Yang
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053616:Janus Kinase 3 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D053683:Oncostatin M / Q000008:administration & dosage*; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D000072483:Placenta Growth Factor; D010929:Placentation; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013582:Synovial Fluid / Q000166:cytology*
chemical_list: C000608036:PGF protein, human; D011257:Pregnancy Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053683:Oncostatin M; D000072483:Placenta Growth Factor; C507933:JAK3 protein, human; D053616:Janus Kinase 3