title: Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection.
abstract: BACKGROUND
  The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor β (TGF-β) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. In order to gain further insight into the pathophysiology of the disorder, we investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS patients from a cohort of 23 patients including 6 patients with novel TGF-β receptor mutations.
  
  
  RESULTS
  We performed gene expression profiling of OECs using microarray analysis followed by quantitative PCR for verification of gene expression. Compared to OECs of age- and sex-matched healthy controls, OECs isolated from three LDS patients displayed altered expression of several genes belonging to the TGF-β pathway, especially those affecting bone morphogenic protein (BMP) signalling including BMP2, BMP4 and BMPR1A. Gene expression of BMP antagonist Gremlin-1 (GREM1) showed the most prominent up-regulation. This increase was confirmed at the protein level by immunoblotting of LDS-OECs. In immunohistochemistry, abundant Gremlin-1 protein expression could be verified in endothelial cells as well as smooth muscle cells within the arterial media. Furthermore, Gremlin-1 plasma levels of LDS patients were significantly elevated compared to healthy control subjects.
  
  
  CONCLUSIONS
  These findings open new avenues in the understanding of the pathogenesis of Loeys-Dietz syndrome and the development of new diagnostic serological methods for early disease detection.
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wellbrock
authors.affiliation: Center of Cardiology and Cardiovascular Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Sheikhzadeh
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Leticia
authors.initials: L
authors.lastname: Oliveira-Ferrer
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Stamm
authors.affiliation: Center of Cardiology and Cardiovascular Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hillebrand
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Keyser
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Klokow
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Vohwinkel
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Bonk
authors.affiliation: Department of Clinical Chemistry/Central Laboratories, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Otto
authors.affiliation: Department of Clinical Chemistry/Central Laboratories, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Division of Hematology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.affiliation: Institute for Neuropathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.affiliation: Center of Cardiology and Cardiovascular Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Rybczynski
authors.affiliation: Department of Transfusion Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bentzien
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Center of Cardiology and Cardiovascular Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Yskert
authors.initials: Y
authors.lastname: von Kodolitsch
authors.affiliation: Hubertus Wald University Cancer Centre, Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
mesh_terms: D000328:Adult; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis / Q000235:genetics; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D042241:Early Diagnosis; D042783:Endothelial Cells / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D053779:Latent TGF-beta Binding Proteins / Q000096:biosynthesis; D055947:Loeys-Dietz Syndrome / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D055815:Young Adult
chemical_list: C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human