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J Cell Sci. 2019 Aug 8;132(15). pii: jcs234948. doi: 10.1242/jcs.234948.

TNAP limits TGF-β-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2/3 transcription factors.

Author information

1
Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
2
Medicines Discovery Catapult, Mereside, Alderley Edge SK104TG, UK.
3
Gubra Hørsholm Kongevej 11B 2970 Hørsholm, Denmark.
4
King's College Hospital, Denmark Hill, London SE5 9RS, UK.
5
Department of Biology, York University, Toronto, ON, M3J 1P3, Canada.
6
TIGET-HSR, Ospedale San Raffele, Via Olgettina 60, 20132 Milan, Italy.
7
Division of Cardiovascular Sciences, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PT, UK.
8
Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK giulio.cossu@manchester.ac.uk.

Abstract

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.

KEYWORDS:

ALPL; Cardiac hypertrophy; Muscular dystrophy; SMAD; Striated muscle fibrosis; TGF-β receptor; Tissue non-specific alkaline phosphatase

PMID:
31289197
DOI:
10.1242/jcs.234948

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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