title: Sclerostin as a potential novel biomarker for aortic valve calcification: an in-vivo and ex-vivo study.
abstract: OBJECTIVE
  Sclerostin is a key negative regulator of bone formation. It was hypothesized that sclerostin might also play a potential role in the development of aortic valve calcification (AVC). The study aim was to evaluate serum sclerostin levels in patients with different degrees of AVC compared to a healthy control group, and to investigate local sclerostin expression in explanted calcified and non-calcified aortic valves.
  
  
  METHODS
  A prospective cross-sectional study was performed in 115 patients (mean age 74 +/- 7 years) with echocardiographically proven AVC. Sclerostin serum levels were measured using ELISA and compared to values obtained from a healthy control population. For quantification of AVC, all patients of the study cohort underwent non-contrast-enhanced dual-source computed tomography (DSCT). Immunohistochemistry (IHC) staining for sclerostin and mRNA sclerostin expression was analyzed in 10 calcified aortic valves and 10 non-calcified age-matched control valves.
  
  
  RESULTS
  Patients with AVC showed significantly higher sclerostin serum levels as compared to healthy controls (0.94 +/- 0.45 versus 0.58 +/- 0.26 ng/ml, p < 0.001). A significant correlation between sclerostin serum levels and Agatston AVC scores as assessed by DSCT was observed (r = 0.62, p < 0.001) in the study cohort. IHC revealed positive sclerostin staining in nine calcified valves, in contrast to negative staining for sclerostin in all non-calcified valves. Quantitative real-time PCR confirmed the increased sclerostin expression on mRNA level, with a significant up-regulation of sclerostin mRNA (fold change 150 +/- 52, p < 0.001) expression being shown in calcified aortic valves compared to non-calcified control valves. Co-staining experiments revealed that sclerostin-expressing cells co-express the major osteogenic transcription factor Runx2 and the extracellular matrix protein osteocalcin.
  
  
  CONCLUSIONS
  Patients with AVC showed increased sclerostin serum levels compared to a healthy reference population, and it was revealed that the severity of AVC may be linked to increased sclerostin serum levels. Moreover, the PCR and staining data demonstrated an increased sclerostin expression in parallel to prototypic markers of osteogenic transdifferentiation, indicating a role of sclerostin in the valvular calcification process.
authors.affiliation: Department of Cardiology, University Hospital RWTH Aachen, RWTH University Aachen, Aachen, Germany. rkoos@ukaachen.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Koos
authors.forename: Vincent
authors.initials: V
authors.lastname: Brandenburg
authors.forename: Andreas Horst
authors.initials: AH
authors.lastname: Mahnken
authors.forename: Rebekka
authors.initials: R
authors.lastname: Schneider
authors.forename: Guido
authors.initials: G
authors.lastname: Dohmen
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Autschbach
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
authors.forename: Rafael
authors.initials: R
authors.lastname: Kramann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000473:pathology / Q000503:physiopathology; D001024:Aortic Valve Stenosis / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000235:genetics; D002114:Calcinosis / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D015150:Echocardiography, Doppler / Q000379:methods; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed / Q000379:methods; D015854:Up-Regulation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human