title: Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification.
abstract: Valvular calcification during calcific aortic stenosis is associated with morphological features of bone formation and expression of various bone-associated proteins, which are both associated with marked leukocyte infiltration of the calcified valve areas. The pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is abundantly present in areas of leukocyte infiltration in stenotic aortic valves. We therefore hypothesized that valvular calcification might be actively regulated by an inflammatory process involving TNF-alpha. Upon stimulation with TNF-alpha, human aortic valve myofibroblasts cultured under mineralizing conditions showed an increased formation of calcified, alkaline phosphatase (ALP)-enriched cell nodules, ALP activity, concentration of the bone-type ALP isoenzyme, and concentration of osteocalcin, all of which are markers of an osteoblast-like cellular phenotype. By electrophoretic mobility shift assay, DNA binding of the essential osteoblastic transcription factor Cbfa-1 was increased compared to untreated controls. These results support the concept that aortic valve calcification is associated with an osteoblast-like phenotype of local myofibroblasts. In addition, the data demonstrate direct mechanistic evidence that aortic valve calcification may be actively regulated by an inflammatory process involving TNF-alpha.
authors.affiliation: 1st Department of Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany. jens.kaden@med.ma.uni-heidelberg.de
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Kaden
authors.forename: Refika
authors.initials: R
authors.lastname: Kiliç
authors.forename: Aslihan
authors.initials: A
authors.lastname: Sarikoç
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hagl
authors.forename: Siegfried
authors.initials: S
authors.lastname: Lang
authors.forename: Ursula
authors.initials: U
authors.lastname: Hoffmann
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckmann
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
mesh_terms: D001021:Aortic Valve / Q000166:cytology* / Q000187:drug effects; D001024:Aortic Valve Stenosis / Q000209:etiology*; D015415:Biomarkers; D002114:Calcinosis / Q000209:etiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D010006:Osteoblasts / Q000166:cytology*; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha