Abstract
BackgroundSclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients.MethodsWe conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 ± 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR).ResultsCAC (Agatston score > 100) and any AVC were present in 65% and in 40% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 ± 0.81 vs 0.76 ± 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 ± 0.84 vs 1.35 ± 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves.ConclusionWe found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.
Highlights
Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover
In order to investigate the association of various biomarkers with Coronary artery calcification (CAC) and aortic valve calcifications (AVC), we studied all exploratory factors in the first instance in a univariate regression model for continuous factors or in an ANOVA model for categorical factors
An in vitro and rodent study by Zhu et al could show that sclerostin is upregulated in experimental models of vascular calcification [33]. We extend these findings for the first time to a potential linkage between sclerostin levels and AVC in humans with end-stage renal disease (ESRD)
Summary
Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. We assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients. CVC constitutes one of the driving forces for the enormously elevated cardiovascular mortality in patients with CKD or end-stage renal disease (ESRD) [3,4]. A novel candidate protein for this bone-vascular axis is sclerostin (22.5 kDa), which is synthesized in osteocytes and is a potent down-regulator of bone metabolism by reducing osteoblast differentiation and function via canonical Wnt-signalling inhibition [13,14]. Recent reports indicated that serum sclerostin levels may reflect reduced bone metabolism and may be useful as marker for low-turnover bone disease in ESRD patient [16]. We hypothesized that sclerostin is linked to vascular calcification in dialysis patients
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