Post-Transcriptional Bone Morphogenetic Protein 2 (BMP2) Gene Regulation in Aorta

Abstract

Deletion of an \"ultra-conserved sequence\" (UCS) within the Bone Morphogenetic Protein (Bmp)2 mRNA previously revealed that the sequence represses Bmp2 reporter gene expression in vascular cells. The objective was to determine the impact of the endogenous UCS on Bmp2 mRNA levels, BMP signaling, and calcification in the healthy control aorta and in the calcified aorta of mice with renal disease. We compared the phenotypes of mice bearing a wild type Bmp2 allele or the UCS deletion allele in mice with normal kidney function or in Klotho mutant mice with reduced kidney function. BMP signaling and calcium levels were normally higher in control females relative to males. UCS deletion induced aortic Bmp2 mRNA and BMP signaling in control males, but not in females. UCS deletion significantly increased BMP signaling in both male and female Klotho homozygotes. Inheritance of the Bmp2 UCS deletion and Klotho alleles was skewed from Mendelian expectations suggesting that these alleles influence interacting pathways. Analyses of body and heart weight supported these interactions. The Bmp2 UCS represses BMP signaling in control males and in mice of both sexes with abnormal mineralization associated with kidney disease. Disease and sex-specific differences in Bmp2 gene control may influence the onset and progression of cardiovascular diseases.