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      Association between Serum Dickkopf-1 (DKK-1) Glycoprotein and Calcific Deposits on Cardiac Valves and Carotid Intimal-Medial Thickness in Hemodialysis Patients

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          Background: Cardiac valve calcification (CVC) is common in hemodialysis (HD) patients, and associated with cardiovascular and all-cause mortality. Once believed to be a passive process, it is now understood that the Wnt signaling pathway has a major role. The aim of the current study was to assess the relationship between circulating DKK-1, a negative regulator of the Wnt signaling pathway, and CVC, as well as carotid intimal-medial thickness (CIMT) in HD patients. Methods: We enrolled 74 consecutive adults on maintenance HD. Echocardiographic calcification of the mitral valve (MV) and aortic valve (AV) were detected according to Wilkins score (range 0–4), and the study of Tenenbaum et al. [Int J Cardiol. 2004 Mar;94(1):7–13] (range 0–4), respectively. CVC severity was calculated by a supposed score (range 0–8) that represents the sum of calcification grade of MV and AV. CVC severity was classified into absent (CVC score = 0), mild (CVC score = 1–2), moderate (CVC score = 3–4), and severe (CVC score ≥5). Demographic and biochemical data were collected in addition to serum DKK-1 levels and CIMT. Results: CVC was present in 67 patients (91.0%). There was a highly significant negative correlation between serum DKK-1 level and CVC score ( r = –0.492; p ≤ 0.001), as well as CIMT ( r = –0.611; p ≤ 0.001). Age and CIMT were independent determinants of CVC. Conclusions: CVC is almost present in all HD patients. DKK-1 seems to have a direct relation with CVC and CIMT in HD patients. Age is the strongest independent determinant of CVC.

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          Most cited references 30

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          American Society of Echocardiography recommendations for use of echocardiography in clinical trials.

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            Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals.

            In diabetic LDLR-/- mice, an ectopic BMP2-Msx2 gene regulatory program is upregulated in association with vascular calcification. We verified the procalcific actions of aortic Msx2 expression in vivo. CMV-Msx2 transgenic (CMV-Msx2Tg(+)) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates. On high-fat diets, CMV-Msx2Tg(+) mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media. This corresponded to regions of Msx2 immunoreactivity in adjacent adventitial myofibroblasts, suggesting a potential paracrine osteogenic signal. To better understand Msx2-regulated calcification, we studied actions in 10T1/2 cells. We found that conditioned media from Msx2-transduced 10T1/2 cells (Msx2-CM) is both pro-osteogenic and adipostatic; these features are characteristic of Wnt signaling. Msx2-CM stimulated Wnt-dependent TCF/LEF transcription, and Msx2-transduced cells exhibited increased nuclear beta-catenin localization with concomitant alkaline phosphatase induction. Msx2 upregulated Wnt3a and Wnt7a but downregulated expression of the canonical inhibitor Dkk1. Dkk1 treatment reversed osteogenic and adipostatic actions of Msx2. Teriparatide, a PTH1R agonist that inhibits murine vascular calcification, suppressed vascular BMP2-Msx2-Wnt signaling. Analyses of CMV-Msx2Tg(+) mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts; moreover, TOPGAL(+) (Wnt reporter); CMV-Msx2Tg(+) mice exhibited augmented aortic LacZ expression. Thus, Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals.
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              CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells.

               Weike Si,  Wen Song,  Hue Luu (2006)
              Marrow mesenchymal stem cells are pluripotent progenitors that can differentiate into bone, cartilage, muscle, and fat cells. Wnt signaling has been implicated in regulating osteogenic differentiation of mesenchymal stem cells. Here, we analyzed the gene expression profile of mesenchymal stem cells that were stimulated with Wnt3A. Among the 220 genes whose expression was significantly changed by 2.5-fold, we found that three members of the CCN family, CCN1/Cyr61, CCN2/connective tissue growth factor (CTGF), and CCN5/WISP2, were among the most significantly up-regulated genes. We further investigated the role of CCN1/Cyr61 in Wnt3A-regulated osteogenic differentiation. We confirmed that CCN1/Cyr61 was up-regulated at the early stage of Wnt3A stimulation. Chromatin immunoprecipitation analysis indicates that CCN1/Cyr61 is a direct target of canonical Wnt/beta-catenin signaling. RNA interference-mediated knockdown of CCN1/Cyr61 expression diminished Wnt3A-induced osteogenic differentiation. Furthermore, exogenously expressed CCN1/Cyr61 was shown to effectively promote mesenchymal stem cell migration. These findings suggest that tightly regulated CCN1/Cyr61 expression may play an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells.

                Author and article information

                Cardiorenal Med
                Cardiorenal Medicine
                S. Karger AG
                September 2020
                08 July 2020
                : 10
                : 5
                : 313-322
                aDepartment of Mansoura Nephrology and Dialysis Unit (MNDU), Mansoura University, Mansoura, Egypt
                bDepartment of Clinical Pathology, Mansoura University, Mansoura, Egypt
                Author notes
                *Dalia Younis, Mansoura Nephrology and Dialysis Unit, Mansoura University, Gomhoria Street, Mansoura 35511 (Egypt),
                507183 Cardiorenal Med 2020;10:313–322
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 3, Pages: 10
                Research Article


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