title: BMP-7 induces TF expression in human monocytes by increasing F3 transcriptional activity.
abstract: BACKGROUND
  Bone morphogenetic protein (BMP)-7, a major regulator of bone metabolism, inhibits ectopic calcification in atherosclerotic plaques. We have recently reported that BMP-7 is also a potent inducer of tissue factor (TF) in human mononuclear cells (MNCs). While nuclear factor kappa beta (NF-kB) and activation protein-1 (AP-1) are the transcription factors essential for inducible expression of human TF gene (F3), the mechanisms responsible for TF induction by BMP-7 are not known.
  
  
  OBJECTIVE
  To elucidate the molecular mechanisms governing BMP-7-triggered TF expression in human MNCs.
  
  
  METHODS
  Human blood monocytes were stimulated with BMP-7 and western blotting, qRT-PCR, and flow cytometry studies were carried out to assess F3 expression; promoter studies were also performed using a panel of reporter constructs. Procoagulant TF activity was measured using a validated FXa generation assay. The significance of NF-kB transcriptional activity was verified via pharmacological inhibition.
  
  
  RESULTS
  BMP-7 increased TF protein levels, procoagulant activity, surface presentation, and TF mRNA expression. This increase was accompanied by activation of NF-kB as evidenced by reduced IkB-α levels and elevated transcriptional activity of an NF-kB-sensitive reporter in transfected MNCs. Although treatment with BMP-7 also led to a strong phosphorylation of c-Jun, activation of AP-1 alone was not sufficient to induce TF expression: JSH-23, a potent and specific NF-kB inhibitor, completely blocked BMP-7-induced TF expression.
  
  
  CONCLUSIONS
  We report that BMP-7-dependent activation of TF in human MNCs is mediated via increased activity of NF-kB, leading to enhanced F3 transcription in human MNCs.
authors.affiliation: K.G. Jebsen Thrombosis and Expertise Centre (TREC), Tromsø, Norway; Hematological Research Group, Department of Clinical Medicine, the Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway; Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA. Electronic address: timofey.sovershaev@uit.no.
authors.forename: T A
authors.initials: TA
authors.lastname: Sovershaev
authors.affiliation: Section for Clinical Pharmacology, University Hospital of North Norway, N-9038, Tromsø, Norway.
authors.forename: E M
authors.initials: EM
authors.lastname: Egorina
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
authors.forename: D
authors.initials: D
authors.lastname: Unruh
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
authors.forename: V Y
authors.initials: VY
authors.lastname: Bogdanov
authors.affiliation: K.G. Jebsen Thrombosis and Expertise Centre (TREC), Tromsø, Norway; Hematological Research Group, Department of Clinical Medicine, the Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, N-9038, Tromsø, Norway.
authors.forename: J B
authors.initials: JB
authors.lastname: Hansen
authors.affiliation: Hematological Research Group, Department of Clinical Medicine, the Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway; Section for Medical Biochemistry, Department of Laboratory Medicine, University Hospital of Northern Norway, N-9038, Tromsø, Norway.
authors.forename: M A
authors.initials: MA
authors.lastname: Sovershaev
mesh_terms: D050197:Atherosclerosis / Q000276:immunology*; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*; D014162:Transfection
chemical_list: D055419:Bone Morphogenetic Protein 7; D013925:Thromboplastin
keywords: Atherogenesis; Bone morphogenetic protein; Coagulation; Monocyte; blood; tissue factor