Reduced sox9 function promotes heart valve calcification phenotypes in vivo. Circ Res 2010 Mar 05;106(4):712-9
Date
01/09/2010Pubmed ID
20056916Pubmed Central ID
PMC2863131DOI
10.1161/CIRCRESAHA.109.213702Scopus ID
2-s2.0-77949388887 (requires institutional sign-in at Scopus site) 103 CitationsAbstract
RATIONALE: Calcification of heart valve structures is the most common form of valvular disease and is characterized by the appearance of bone-like phenotypes within affected structures. Despite the clinical significance, the underlying etiology of disease onset and progression is largely unknown and valve replacement remains the most effective treatment. The SRY-related transcription factor Sox9 is expressed in developing and mature heart valves, and its function is required for expression of cartilage-associated proteins, similar to its role in chondrogenesis. In addition to cartilage-associated defects, mice with reduced sox9 function develop skeletal bone prematurely; however, the ability of sox9 deficiency to promote ectopic osteogenic phenotypes in heart valves has not been examined.
OBJECTIVE: This study aims to determine the role of Sox9 in maintaining connective tissue homeostasis in mature heart valves using in vivo and in vitro approaches.
METHODS AND RESULTS: Using histological and molecular analyses, we report that, from 3 months of age, Sox9(fl/+);Col2a1-cre mice develop calcific lesions in heart valve leaflets associated with increased expression of bone-related genes and activation of inflammation and matrix remodeling processes. Consistently, ectopic calcification is also observed following direct knockdown of Sox9 in heart valves in vitro. Furthermore, we show that retinoic acid treatment in mature heart valves is sufficient to promote calcific processes in vitro, which can be attenuated by Sox9 overexpression.
CONCLUSIONS: This study provides insight into the molecular mechanisms of heart valve calcification and identifies reduced Sox9 function as a potential genetic basis for calcific valvular disease.
Author List
Peacock JD, Levay AK, Gillaspie DB, Tao G, Lincoln JAuthor
Joy Lincoln PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Age FactorsAging
Animals
Animals, Newborn
Calcinosis
Calcium
Chick Embryo
Collagen Type II
Disease Models, Animal
Down-Regulation
Extracellular Matrix
Female
Gene Knockdown Techniques
Genotype
Heart Valve Diseases
Inflammation
Integrases
Male
Mice
Mice, Transgenic
Mitral Valve
Osteogenesis
Phenotype
SOX9 Transcription Factor
Tissue Culture Techniques
Transfection
Tretinoin
Tricuspid Valve