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GREM1 Is a Key Regulator of Synoviocyte Hyperplasia and Invasiveness
- GREM1 Is a Key Regulator of Synoviocyte Hyperplasia and Invasiveness
- 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
- Journal of Rheumatology, 43(3), 474-485
- Article Type
- Alpha v Beta3 Integrin; Apoptosis; Apoptosis Assay; Cell Invasion; Cell Invasion Assay; Cell Migration; Cell Proliferation; Cell Survival; Colorimetry; Controlled Study; Down-Regulation; Enzyme Linked Immunosorbent Assay; Fibroblast Like Synoviocyte; Fibroblastibroblast-Like Synoviocytes; Gene; Gene Expression Profiling; Gene Identification; GREM1 Gene; Gremlin 1; Human; Human Cell; Human Tissue; Immunohistochemistry; Major Clinical Study; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neutralizing Antibody; Osteoarthritis; Pathogenesis; Priority Journal; Protein Bax; Protein BCL 2; Real Time Polymerase Chain Reaction; Rheumatoid Arthritis; Small Interfering Rna; Synoviocyte; Tetrazolium; Vitronectin Receptor; Western Blotting
- 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.
- Journal of Rheumatology Publishing Company
- Related Researcher
Hwang, Dae Hee
Systems Biology and Medicine Lab
Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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- Department of New BiologySystems Biology and Medicine Lab1. Journal Articles
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