Open AccessNF‐AT5 is a critical regulator of inflammatory arthritis
Author(s) -
Yoon HyungJu,
You Sungyong,
Yoo SeungAh,
Kim NamHoon,
Kwon H. Moo,
Yoon ChongHyeon,
Cho ChulSoo,
Hwang Daehee,
Kim WanUk
Publication year - 2011
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30229
Subject(s) - angiogenesis , proinflammatory cytokine , small interfering rna , arthritis , cancer research , vascular endothelial growth factor , tumor necrosis factor alpha , medicine , synovial membrane , human umbilical vein endothelial cell , immunology , umbilical vein , transfection , inflammation , biology , cell culture , in vitro , biochemistry , vegf receptors , genetics
Objective To investigate the role of NF‐AT5, an osmoprotective transcription factor, in synovial hyperplasia and angiogenesis in patients with rheumatoid arthritis (RA). Methods The expression of NF‐AT5 in synovial tissue and synoviocytes from RA patients was examined by immunohistochemistry and Western blot analysis, respectively. Messenger RNA (mRNA) in RA synoviocytes and human umbilical vein endothelial cells (HUVECs) transfected with dummy small interfering RNA (siRNA) or NF‐AT5 siRNA were profiled using microarray technology. Assays to determine synoviocyte apoptosis and proliferation were performed in the presence of NF‐AT5 siRNA. VEGF 165 ‐induced angiogenesis was assessed by measuring the proliferation, tube formation, and wound migration of HUVECs. Experimental arthritis was induced in mice by injection of anti–type II collagen antibody. Results NF‐AT5 was highly expressed in rheumatoid synovium, and its activity was increased by proinflammatory cytokines, such as interleukin‐1β and tumor necrosis factor α. The mRNA profiling of synoviocytes and HUVECs transfected with NF‐AT5–targeted siRNA revealed 3 major changes in cellular processes associated with the pathogenesis of RA: cell cycle and survival, angiogenesis, and cell migration. Consistent with these results, NF‐AT5 knockdown in RA synoviocytes and HUVECs inhibited their proliferation/survival and impeded angiogenic processes in HUVECs. Mice with NF‐AT5 haploinsufficiency (NF‐AT5 +/– ) developed a very limited degree of synovial proliferation, as seen on histologic analysis, and decreased angiogenesis, and they exhibited a nearly complete suppression of experimentally induced arthritis. Conclusion NF‐AT5 regulates synovial proliferation and angiogenesis in chronic arthritis.