Bone Abstracts (2014) 3 PP384 | DOI: 10.1530/boneabs.3.PP384

Wnt16 as a new regulator of vascular calcification

Maria Nurminskaya & Kelly Beazley


University of Maryland, Baltimore, Maryland, USA.


Objective: Vascular calcification contributes to the pathogenesis of atherosclerosis, hypercholesterolemia, end stage renal disease, and diabetes, and is caused by genetic ablation of matrix Gla protein (MGP) in mice. Genetic ablation of MGP in mice results in excessive calcification of the vessel wall associated with a chondrocyte-like trans-differentiation in smooth muscle cells (VSMCs). Canonical β-catenin signaling is activated in the calcified arterial Mgp−/− tissue, however expression of Wnt16 is down-regulated almost 20-fold. The expression pattern of Wnt16 in embryonic bone development suggests its antagonistic function in chondrogenic differentiation and recent studies indicate a role for Wnt16 as a regulator of Notch signaling. The objective if this study was to determine whether and how Wnt16 controls phenotypic stability in VSMCs.

Methods: Primary WT and MGP−/− VSMCs were induced to undergo chondrogenesis in high-density micromasses in the presence or absence of overexpressed Wnt16.

Results: Expression of Wnt16 decreases with chondrogenic transformation in WT VSMCs. Primary MGP−/− VSMCs that have reduced levels of Wnt16 expression undergo spontaneous chondrogenesis in the absence of common inducer TGFβ. Overexpression of Wnt16 prevents chondrogenesis in both WT and MGP−/− VSMCs. Accordingly, Notch signaling is inactivated with chondrogenesis and loss of MGP expression in VSMCs, and forced expression of Wnt16 activates this signaling.

Conclusions: The Wnt16–Notch signaling network supports phenotypic stability in VSMCs and prevents their chondrogenic transformation. These results identify Wnt16 as a new therapeutic approach to vascular calcification, and may contribute to the understanding of its role in embryonic bone development.

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