title: Loss of β-catenin promotes chondrogenic differentiation of aortic valve interstitial cells.
abstract: OBJECTIVE
  The Wnt/β-catenin signaling pathway has been implicated in human heart valve disease and is required for early heart valve formation in mouse and zebrafish. However, the specific functions of Wnt/β-catenin signaling activity in heart valve maturation and maintenance in adults have not been determined previously.
  
  
  RESULTS
  Here, we show that Wnt/β-catenin signaling inhibits Sox9 nuclear localization and proteoglycan expression in cultured chicken embryo aortic valves. Loss of β-catenin in vivo in mice, using Periostin(Postn)Cre-mediated tissue-restricted loss of β-catenin (Ctnnb1) in valvular interstitial cells, leads to the formation of aberrant chondrogenic nodules and induction of chondrogenic gene expression in adult aortic valves. These nodular cells strongly express nuclear Sox9 and Sox9 downstream chondrogenic extracellular matrix genes, including Aggrecan, Col2a1, and Col10a1. Excessive chondrogenic proteoglycan accumulation and disruption of stratified extracellular matrix maintenance in the aortic valve leaflets are characteristics of myxomatous valve disease. Both in vitro and in vivo data demonstrate that the loss of Wnt/β-catenin signaling leads to increased nuclear expression of Sox9 concomitant with induced expression of chondrogenic extracellular matrix proteins.
  
  
  CONCLUSIONS
  β-Catenin limits Sox9 nuclear localization and inhibits chondrogenic differentiation during valve development and in adult aortic valve homeostasis.
authors.affiliation: From the Heart Institute, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.).
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.affiliation: From the Heart Institute, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.).
authors.forename: Christina M
authors.initials: CM
authors.lastname: Alfieri
authors.affiliation: From the Heart Institute, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.).
authors.forename: Alexia
authors.initials: A
authors.lastname: Hulin
authors.affiliation: From the Heart Institute, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.).
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: From the Heart Institute, Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, OH (M.F., C.M.A., A.H., K.E.Y.); and Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (S.J.C.). katherine.yutzey@cchmc.org.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Yutzey
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000166:cytology* / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D030161:Avian Proteins / Q000378:metabolism; D000082882:Bicuspid Aortic Valve Disease; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002642:Chick Embryo; D020219:Chondrogenesis / Q000235:genetics / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006349:Heart Valve Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011509:Proteoglycans / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D030161:Avian Proteins; C495267:CTNNB1 protein, mouse; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D055758:SOX9 Transcription Factor; D051176:beta Catenin
keywords: Wnt signaling pathway; aortic valve; chondrogenesis; heart valve disease; proteoglycans