Submitted on May 4, 2009
Revised on August 18, 2009
Accepted on August 25, 2009
Lack of periostin leads to suppression of Notch1 signaling and calcific aortic valve disease
Tatiana V. Tkatchenko1, Ricardo A. Moreno-Rodriguez2, Simon J. Conway3, Jeffery D Molkentin4, Roger R. Markwald2, and Andrei V. Tkatchenko1*
1 Wayne State University
2 Medical University of South Carolina
3 Indiana University School of Medicine
4 Children's Hospital Medical Center
* To whom correspondence should be addressed. E-mail: atkatche{at}med.wayne.edu.
The Postn gene encodes protein periostin. During embryonic development, it is highly expressed in the outflow track (OFT) endocardial cushions of the developing heart, which give rise to several structures of the mature heart including aortic valve. Periostin was previously implicated in osteoblast differentiation, cancer metastasis, teeth and bone development, but its role in cardiac OFT development is unclear. To elucidate the role periostin plays in developing heart we have analyzed cardiac OFT phenotype in mice after deletion of the Postn gene. We found that lack of periostin in the embryonic OFT leads to ectopic expression of a pro-osteogenic growth factor pleiotrophin (Ptn) and overexpression of delta-like 1 homolog (Dlk1), a negative regulator of Notch1, in the distal (prevalvular) cushions of the OFT. This resulted in suppression of Notch1 signaling, strong induction of the central transcriptional regulator of osteoblast cell fate Runx2, up-regulation of osteopontin and osteocalcin expression, and subsequent calcification of the aortic valve. Our data suggest that periostin represses a default osteogenic program in the OFT cushion mesenchyme and promotes their differentiation along a fibrogenic lineage. Lack of periostin causes de-repression of the osteogenic potential of OFT mesenchymal cells, calcium deposition and calcific aortic valve disease. These results establish periostin as a key regulator of the OFT endocardial cushion mesenchymal cell fate during embryonic development.
