Mechanobiology

Sclerostin ablation prevents aortic valve stenosis in mice

AUTHORS

ABSTRACT

OBJECTIVE: To test the hypothesis that targeting sclerostin would accelerate the progression of aortic valve stenosis.

BACKGROUND: Sclerostin (gene: Sost) is a secreted glycoprotein that acts as a potent regulator of bone remodeling. Antibody therapy targeting sclerostin is approved for osteoporosis but results from a stage 3 clinical trial showed multiple off-target cardiovascular effects.

METHODS: Mice with wild-type (WT) and null (NULL) expression of the Sost gene were generated and maintained to 12 months of age on a high-cholesterol diet to induce aortic valve stenosis. Mice were examined by echocardiography, histology, and RNAseq. Immortalized valve interstitial cells were developed from each genotype for in vitro studies.

RESULTS: NULL mice developed a bone overgrowth phenotype, similar to sclerosteosis patients. Surprisingly however, WT mice developed hemodynamic signs of aortic valve stenosis while NULL mice were unchanged. WT mice had thicker aortic valve leaflets and higher amounts of ɑ-smooth muscle actin, a marker myofibroblast activation and dystrophic calcification, with very little evidence of Runx2 expression, a marker of osteogenic calcification. RNAseq analysis of aortic roots indicated the HOX family of transcription factors were significantly upregulated in NULL mice, and valve interstitial cells from NULL animals were enriched with Hoxa1, Hoxb2, and Hoxd3 subtypes with downregulated Hoxa7. Additionally, NULL valve interstitial cells were shown to be less contractile than their WT counterparts.

CONCLUSION: Contrary to our hypothesis, sclerostin targeting prevented hallmarks of aortic valve stenosis and indicate that targeted antibody treatments for osteoporosis may be beneficial for these patients regarding aortic stenosis.