title: GREM1 Is a Key Regulator of Synoviocyte Hyperplasia and Invasiveness.
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 ανβ3 integrin on RA-FLS, suggesting that ανβ3 integrin mediates the antiapoptotic and promigratory effects of GREM1.
  
  
  CONCLUSIONS
  GREM1 is highly expressed in RA joints, and functions as a regulator of survival, proliferation, migration, and invasion of RA-FLS.
authors.affiliation: From the POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea, Seoul; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea; Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.E.J. Han, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S.A. Yoo, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; G.M. Kim, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; D. Hwang, PhD, Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST; C.S. Cho, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S. You, PhD, Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; W.U. Kim, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Han
authors.affiliation: From the POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea, Seoul; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea; Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.E.J. Han, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S.A. Yoo, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; G.M. Kim, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; D. Hwang, PhD, Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST; C.S. Cho, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S. You, PhD, Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; W.U. Kim, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.affiliation: From the POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea, Seoul; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea; Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.E.J. Han, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S.A. Yoo, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; G.M. Kim, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; D. Hwang, PhD, Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST; C.S. Cho, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S. You, PhD, Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; W.U. Kim, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea.
authors.forename: Gi-Myo
authors.initials: GM
authors.lastname: Kim
authors.affiliation: From the POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea, Seoul; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea; Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.E.J. Han, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S.A. Yoo, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; G.M. Kim, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; D. Hwang, PhD, Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST; C.S. Cho, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S. You, PhD, Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; W.U. Kim, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: From the POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea, Seoul; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea; Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.E.J. Han, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S.A. Yoo, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; G.M. Kim, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; D. Hwang, PhD, Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST; C.S. Cho, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S. You, PhD, Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; W.U. Kim, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea.
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.affiliation: From the POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea, Seoul; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea; Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.E.J. Han, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S.A. Yoo, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; G.M. Kim, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; D. Hwang, PhD, Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST; C.S. Cho, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S. You, PhD, Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; W.U. Kim, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea. wan725@catholic.ac.kr Sungyong.You@cshs.org.
authors.forename: Sungyong
authors.initials: S
authors.lastname: You
authors.affiliation: From the POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea, Seoul; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea; Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.E.J. Han, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S.A. Yoo, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; G.M. Kim, PhD Candidate, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; D. Hwang, PhD, Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, DGIST; C.S. Cho, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, Catholic University of Korea; S. You, PhD, Department of Surgery and Biomedical Sciences, Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; W.U. Kim, MD, PhD, POSTECH-CATHOLIC Biomedical Engineering Institute, and Department of Internal Medicine, Catholic University of Korea. wan725@catholic.ac.kr Sungyong.You@cshs.org.
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D000070918:Synoviocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins
keywords: FIBROBLAST-LIKE SYNOVIOCYTES; GREMLIN 1; RHEUMATOID ARTHRITIS; ανβ3 INTEGRIN