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NF-AT5 is a critical regulator of inflammatory arthritis.
- Source :
-
Arthritis and rheumatism [Arthritis Rheum] 2011 Jul; Vol. 63 (7), pp. 1843-52. - Publication Year :
- 2011
-
Abstract
- Objective: To investigate the role of NF-AT5, an osmoprotective transcription factor, in synovial hyperplasia and angiogenesis in patients with rheumatoid arthritis (RA).<br />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. VEGF₁₆₅-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.<br />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.<br />Conclusion: NF-AT5 regulates synovial proliferation and angiogenesis in chronic arthritis.<br /> (Copyright © 2011 by the American College of Rheumatology.)
- Subjects :
- Arthritis, Rheumatoid genetics
Arthritis, Rheumatoid pathology
Blotting, Western
Cell Proliferation
Endothelial Cells drug effects
Endothelial Cells metabolism
Endothelial Cells pathology
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Interleukin-1beta metabolism
Interleukin-1beta pharmacology
NFATC Transcription Factors genetics
Neovascularization, Pathologic genetics
Neovascularization, Pathologic pathology
RNA, Messenger genetics
RNA, Messenger metabolism
RNA, Small Interfering
Statistics, Nonparametric
Synovial Membrane drug effects
Synovial Membrane pathology
Transfection
Tumor Necrosis Factor-alpha metabolism
Tumor Necrosis Factor-alpha pharmacology
Arthritis, Rheumatoid metabolism
NFATC Transcription Factors metabolism
Neovascularization, Pathologic metabolism
Synovial Membrane metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-0131
- Volume :
- 63
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Arthritis and rheumatism
- Publication Type :
- Academic Journal
- Accession number :
- 21717420
- Full Text :
- https://doi.org/10.1002/art.30229