RT Journal Article
SR Electronic
T1 TNAP limits TGF-β-dependent cardiac and skeletal muscle fibrosis by inactivating SMAD2/3 transcription factors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 655332
DO 10.1101/655332
A1 Benedetta Arnò
A1 Francesco Galli
A1 Urmas Roostalu
A1 Bashar Aldeiri
A1 Tetsuaki Miyake
A1 Alessandra Albertini
A1 Laricia Bragg
A1 Sukhpal Prehar
A1 John C. McDermott
A1 Elizabeth J. Cartwright
A1 Giulio Cossu
YR 2019
UL http://biorxiv.org/content/early/2019/05/30/655332.abstract
AB Fibrosis is associated with almost all forms of chronic cardiac and skeletal muscle diseases. The accumulation of extracellular matrix impairs the contractility of muscle cells contributing to organ failure. Transforming growth factor beta (TGF-β) plays a pivotal role in fibrosis, activating pro-fibrotic gene programs via phosphorylation of SMAD2/3 transcription factors. However, the mechanisms that control de-phosphorylation of SMAD2/3 have remained poorly characterized. Here we show that tissue non-specific alkaline phosphatase (TNAP) is highly upregulated in hypertrophic hearts and in dystrophic skeletal muscles, and the abrogation of TGF-β signalling in TNAP positive cells reduces vascular and interstitial fibrosis. We show that TNAP co-localizes and interacts with SMAD2. TNAP inhibitor MLS-0038949 increases SMAD2/3 phosphorylation, while TNAP overexpression reduces SMAD2/3 phosphorylation and the expression of downstream fibrotic genes. Overall our data demonstrate that TNAP negatively regulates TGF-β signalling and likely represents a mechanism to limit fibrosis.Summary statement This paper shows that tissue non-specific alkaline phosphatase negatively regulates TGF-β signalling and may represent a mechanism to limit fibrosis through SMAD dephosphorylation.