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

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 11

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Working model of Msx2 actions during vascular calcification. High-fat di...
Working model of Msx2 actions during vascular calcification. High-fat diets upregulate aortic BMP2 expression (10). In addition to providing progenitors for medial disease processes (40, 41, 43), Msx2-expressing adventitial myofibroblasts produce an osteogenic milieu via induction of Wnt agonists and inhibition of the LRP5/6 antagonist, Dkk1. This causes nuclear localization and activation of β-catenin — an indispensable coregulator of osteoblast differentiation and mineralization (24); as reflected by TCF/LEF-dependent transcription, activation occurs in a subset of medial CVCs. CVCs of Demer (50), perhaps derived from migratory adventitial progenitors (10, 40, 41, 43), respond by upregulating ALP expression via key osteogenic transcription factors (11). Vascular PTH1R signaling dampens Msx2-Wnt signaling. In ESRD, PTH1R downregulation (desensitization) arising from hyperparathyroidism may accelerate vascular disease. Although Osx is upregulated by Msx2 (10), the relationship between β-catenin:TCF/LEF signaling (24) and Osx (60) in mineralization has yet to be clarified. The pyrophosphate-generating (PPi-generating) enzyme ENPP1 inhibits arterial calcification, stabilizing the VSMC phenotype (55).