title: Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis.
abstract: OBJECTIVE
  Aortic valve sclerosis (AVSc) is a hallmark of several cardiovascular conditions ranging from chronic heart failure and myocardial infarction to calcific aortic valve stenosis (AVS). AVSc, present in 25-30% of patients over 65 years of age, is characterized by thickening of the leaflets with marginal effects on the mechanical proprieties of the valve making its presentation asymptomatic. Despite its clinical prevalence, few studies have investigated the pathogenesis of this disease using human AVSc specimens. Here, we investigate in vitro and ex vivo BMP4-mediated transdifferentiation of human valve interstitial cells (VICs) towards an osteogenic-like phenotype in AVSc.
  
  
  RESULTS
  Human specimens from 60 patients were collected at the time of aortic valve replacement (AVS) or through the heart transplant programme (Controls and AVSc). We show that non-calcified leaflets from AVSc patients can be induced to express markers of osteogenic transdifferentiation and biomineralization through the combinatory effect of BMP4 and mechanical stimulation. We show that BMP4 antagonist Noggin attenuates VIC activation and biomineralization. Additionally, patient-derived VICs were induced to transdifferentiate using either cell culture or a Tissue Engineering (TE) Aortic Valve model. We determine that while BMP4 alone is not sufficient to induce osteogenic transdifferentiation of AVSc-derived cells, the combinatory effect of BMP4 and mechanical stretch induces VIC activation towards a phenotype typical of late calcified stage of the disease.
  
  
  CONCLUSIONS
  This work demonstrates, for the first time using AVSc specimens, that human sclerotic aortic valves can be induced to express marker of osteogenic-like phenotype typical of advanced severe aortic stenosis.
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Poggio
authors.forename: Rachana
authors.initials: R
authors.lastname: Sainger
authors.forename: Emanuela
authors.initials: E
authors.lastname: Branchetti
authors.forename: Juan B
authors.initials: JB
authors.lastname: Grau
authors.forename: Eric K
authors.initials: EK
authors.lastname: Lai
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gorman
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sacks
authors.forename: Alessandro
authors.initials: A
authors.lastname: Parolari
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Bavaria
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrari
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019149:Bioreactors; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D040542:Mechanotransduction, Cellular; D008875:Middle Aged; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D011312:Pressure; D011994:Recombinant Proteins / Q000378:metabolism; D012598:Sclerosis; D046509:Tissue Culture Techniques; D023822:Tissue Engineering / Q000379:methods; D054457:Tissue Scaffolds; D055815:Young Adult; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D011994:Recombinant Proteins; D000099176:Noggin Protein; C525809:BMP4 protein, human
keywords: Aortic valve sclerosis; Bone morphogenetic protein 4; Calcific aortic stenosis; Valve interstitial cells