Loss of Axin2 leads to Myxomatous Valve Disease

In the older population, myxomatous valve disease (MVD) is the second most common heart valve disease and the leading cause of mitral regurgitation. Myxomatous valves display thickened leaflets with glycosaminoglycan (GAG) accumulation and increased chondrogenic markers, such as Sox9 and aggrecan. Recent human microarray data suggest activation of Wnt/β‐catenin signaling in MVD. However, the role of Wnt/β‐catenin signaling in the pathogenesis of MVD is still poorly understood. To further investigate the role of Wnt/β‐catenin signaling, we analyzed heart valves from mice deficient in Axin2, a negative regulator of Wnt/β‐catenin signaling. Axin2 is expressed in endothelial and interstitial cells in adult heart valves as indicated by X‐gal staining of Axin2‐lacZ heterozygous mice. Homozygous loss of Axin2 (KO) does not impair early heart valve development. However, at birth and in adult mice, KO mice demonstrate thickened GAG‐rich aortic valves with increased cell proliferation and nuclear Sox9. At 4 months, focal aggrecan‐rich areas are observed along with increased TGF‐β and BMP signaling, as indicated by increased phosphorylation of Smad2/3 and Smad1/5/9 respectively. These features are consistent with human myxomatous mitral valves. Moreover, thickened aortic valves do not calcify as indicated by lack of alizarin red staining in 1 year old KO mice. Interestingly, melanocyte accumulation is also observed in thickened aortic valves, suggesting that Axin2 may influence neural crest cell contributions to heart valves. Ongoing in vivo and in vitro studies are investigating the specific functions of Axin2 in valve disease mechanisms. Altogether these data indicate a role for Axin2 in heart valve homeostasis and in myxomatous disease. In addition, the Axin2‐deficient mouse is a new model for myxomatous valve disease that will be used to decipher molecular pathway interactions and identify therapeutic targets in valve pathogenesis.