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Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals
Jian-Su Shao, … , Arleen P. Loewy, Dwight A. Towler
Jian-Su Shao, … , Arleen P. Loewy, Dwight A. Towler
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1210-1220. https://doi.org/10.1172/JCI24140.
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Article Cardiology

Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals

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Abstract

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 β-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.

Authors

Jian-Su Shao, Su-Li Cheng, Joyce M. Pingsterhaus, Nichole Charlton-Kachigian, Arleen P. Loewy, Dwight A. Towler

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Figure 1

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Enhanced cardiovascular calcification in CMV-Msx2Tg+ mice. Mice transgen...
Enhanced cardiovascular calcification in CMV-Msx2Tg+ mice. Mice transgenic for Msx2 expression were generated as described in Methods. A total of 12 male siblings (6 CMV-Msx2Tg+, 6 nontransgenic, C57BL/6 background) were placed on high-fat diets for 4 months, sacrificed, and analyzed for cardiovascular calcification by alizarin red histochemistry. Five of 6 CMV-Msx2Tg+ mice exhibited cardiovascular calcium deposition (A), while none of the nontransgenic wild-type siblings were significantly afflicted (B). Note the pronounced calcium staining in the tunica media of the left coronary artery (LCA) and aorta, the right ventricular myocardium, and the pulmonary outflow tract. Magnification, ×100. (C) CMV-Msx2Tg+. Higher-power magnification of panel A, ×400. Note marked calcification associated with cells of the tunica media (arrows) and the occasional much weaker and diffuse staining in the adventitia (arrowhead).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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