title: Inhibition of bone morphogenetic protein signal transduction prevents the medial vascular calcification associated with matrix Gla protein deficiency.
abstract: OBJECTIVE
  Matrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice.
  
  
  RESULTS
  MGP-deficient mice (MGP(-/-)) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP(-/-) mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP(-/-) mice survived longer than vehicle-treated MGP(-/-) mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP(-/-) and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP(-/-) aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189.
  
  
  CONCLUSIONS
  Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP(-/-) mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice.
authors.affiliation: Cardiovascular Research Center and Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Malhotra
authors.affiliation: Cardiovascular Research Center and Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Megan F
authors.initials: MF
authors.lastname: Burke
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Trejeeve
authors.initials: T
authors.lastname: Martyn
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Shakartzi
authors.affiliation: Cardiovascular Research Center and Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Thayer
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Caitlin
authors.initials: C
authors.lastname: O'Rourke
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Pingcheng
authors.initials: P
authors.lastname: Li
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America; Department of Anesthesiology, Uniklinik Aachen, RWTH Aachen University, Aachen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Derwall
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Ester
authors.initials: E
authors.lastname: Spagnolli
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Starsha A
authors.initials: SA
authors.lastname: Kolodziej
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Konrad
authors.initials: K
authors.lastname: Hoeft
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Mayeur
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Pawina
authors.initials: P
authors.lastname: Jiramongkolchai
authors.affiliation: Acceleron Pharma, Inc. Cambridge, MA, United States of America.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.affiliation: Cardiovascular Research Center and Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America; Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America; Center for Immunology and Inflammatory Diseases and the Division of Rheumatology, Allergy, and Immunology of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bloch
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D051379:Mice; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D061205:Vascular Calcification / Q000188:drug therapy* / Q000235:genetics; D000097568:Matrix Gla Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D000097568:Matrix Gla Protein; C554430:LDN 193189