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GREM1 Is a Key Regulator of Synoviocyte Hyperplasia and Invasiveness

Title
GREM1 Is a Key Regulator of Synoviocyte Hyperplasia and Invasiveness
Authors
Han, EJ[Han, Eun-Jin]Yoo, SA[Yoo, Seung-Ah]Kim, GM[Kim, Gi-Myo]Hwang, D[Hwang, Daehee]Cho, CS[Cho, Chul-Soo]You, S[You, Sungyong]Kim, WU[Kim, Wan-Uk]
DGIST Authors
Hwang, D[Hwang, Daehee]
Issue Date
2016-03
Citation
Journal of Rheumatology, 43(3), 474-485
Type
Article
Article Type
Article
Keywords
Alpha v Beta3 IntegrinApoptosisApoptosis AssayCell InvasionCell Invasion AssayCell MigrationCell ProliferationCell SurvivalColorimetryControlled StudyDown-RegulationEnzyme Linked Immunosorbent AssayFibroblast Like SynoviocyteFibroblastibroblast-Like SynoviocytesGeneGene Expression ProfilingGene IdentificationGREM1 GeneGremlin 1HumanHuman CellHuman TissueImmunohistochemistryMajor Clinical StudyMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Neutralizing AntibodyOsteoarthritisPathogenesisPriority JournalProtein BaxProtein BCL 2Real Time Polymerase Chain ReactionRheumatoid ArthritisSmall Interfering RnaSynoviocyteTetrazoliumVitronectin ReceptorWestern Blotting
ISSN
0315-162X
Abstract
Objective. To investigate the expression of Gremlin 1 (GREM1), an antagonist of bone morphogenetic protein, in rheumatoid arthritis (RA) synovia and its involvement in the hyperplasia and invasiveness of fibroblast-like synoviocytes of RA (RA-FLS). Methods. Computational analysis was introduced to identify FLS-predominant regulators. GREM1 expression was examined by immunohistochemistry, real-time PCR, and ELISA. FLS proliferation and apoptosis were determined using tetrazolium-based colorimetric assay and APOPercentage assay, respectively. FLS migration and invasion were evaluated by wound migration and Matrigel invasion assay, respectively. Expressions of Bax, Bcl2, pErk1/2, and pAkt were detected by Western blot analysis. Results. Through global transcriptome profiling, we identified a GREM1 gene predominantly expressed in RA-FLS. Indeed, the GREM1 expression was higher in synovia, synovial fluids, and FLS of patients with RA than in those of patients with osteoarthritis, and its levels correlated well with proinflammatory cytokine concentrations. Knockdown of GREM1 transcripts using short interfering RNA (siRNA) reduced the proliferation and survival of RA-FLS along with downregulation of pErk1/2, pAkt, and Bcl2 expressions, whereas it induced Bax expression. Conversely, the addition of recombinant GREM1 to RA-FLS showed the opposite results. Moreover, GREM1 siRNA decreased the migratory and invasive capacity of RA-FLS, whereas exogenous GREM1 increased it. The GREM1-induced FLS survival, migration, and invasion were completely blocked by neutralizing antibodies to αvβ3 integrin on RA-FLS, suggesting that αvβ3 integrin mediates the antiapoptotic and promigratory effects of GREM1. Conclusion. GREM1 is highly expressed in RA joints, and functions as a regulator of survival, proliferation, migration, and invasion of RA-FLS. Copyright © 2016 The Journal of Rheumatology. All rights reserved.
URI
http://hdl.handle.net/20.500.11750/2715
DOI
10.3899/jrheum.150523
Publisher
Journal of Rheumatology Publishing Company
Related Researcher
  • Author Hwang, Dae Hee Systems Biology and Medicine Lab
  • Research Interests Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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Collection:
New BiologyETC1. Journal Articles


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