TNAP limits TGF-β-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2/3 transcription factors.
Benedetta ArnòFrancesco GalliUrmas RoostaluBashar M AldeiriTetsuaki MiyakeAlessandra AlbertiniLaricia BraggSukhpal PreharJohn C McDermottElizabeth J CartwrightGiulio CossuPublished in: Journal of cell science (2019)
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 β (TGF-β) plays a pivotal role in fibrosis, activating pro-fibrotic gene programmes via phosphorylation of SMAD2/3 transcription factors. However, the mechanisms that control de-phosphorylation of SMAD2 and SMAD3 (SMAD2/3) have remained poorly characterized. Here, we show that tissue non-specific alkaline phosphatase (TNAP, also known as ALPL) is highly upregulated in hypertrophic hearts and in dystrophic skeletal muscles, and that the abrogation of TGF-β signalling in TNAP-positive cells reduces vascular and interstitial fibrosis. We show that TNAP colocalizes and interacts with SMAD2. The 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.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- skeletal muscle
- transcription factor
- extracellular matrix
- induced apoptosis
- signaling pathway
- poor prognosis
- cell cycle arrest
- left ventricular
- systemic sclerosis
- genome wide
- insulin resistance
- gene expression
- cell proliferation
- genome wide identification
- metabolic syndrome
- binding protein
- type diabetes
- endoplasmic reticulum stress
- dna binding
- cell death
- copy number
- dna methylation
- big data
- atrial fibrillation
- long non coding rna
- anti inflammatory