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Constitutively activated dystrophic muscle fibroblasts show a paradoxical response to TGF-β and CTGF/CCN2

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Transforming growth factor beta (TGF-β) and connective tissue growth factor (CTGF) have been described to induce the production of extracellular matrix (ECM) proteins and have been reported to be increased in different fibrotic disorders. Skeletal muscle fibrosis is a common feature of Duchenne muscular dystrophy (DMD). The mdx mouse diaphragm is a good model for DMD since it reproduces the muscle degenerative and fibrotic changes. Fibronectin (FN) and proteoglycans (PG) are some of the ECM proteins upregulated in dystrophic conditions. In view of understanding the fibrotic process involved in DMD we have isolated fibroblasts from dystrophic mdx diaphragms. Here we report that regardless of the absence of degenerative myofibers, adult mdx diaphragm fibroblasts show increased levels of FN and condroitin/dermatan sulfate PGs synthesis. Fibroblasts isolated from non fibrotic tissue, such as 1 week old mice diaphragms or skin, do not present elevated FN levels. Furthermore, mdx fibroblast conditioned media is able to stimulate FN synthesis in control fibroblasts. Autocrine TGF-β signaling was unaltered in mdx cells. When control fibroblasts are exposed to TGF-β and CTGF, FN increases as expected. Paradoxically, in mdx cells it decreases in a concentration dependent manner and this decrease is not due to a downregulation of FN synthesis. According to this data we hypothesize that a pathological environment is able to reprogram fibroblasts into an activated phenotype which can be maintained through generations.

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Abbreviations

α-SMA:

Alpha smooth muscle actin

CABC :

Chondroitinase ABC

CTGF/CCN2:

Connective tissue growth factor

DMD:

Duchenne muscular dystrophy

ECM:

Extracellular matrix

FN:

Fibronectin

Hase :

Heparitinase

PGs:

Proteoglycans

TGF-β:

Transforming growth factor type β

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Acknowledgements

This work was supported in part by grants from FONDAP-Biomedicine No. 13980001, CONICYT AT-24050106 and MDA 3790. The research of E.B. was supported in part by an International Research Scholar grant from the Howard Hughes Medical Institute. V.M. was financed in part by CONICYT and MECESUP. C.V. was financed by CONICYT. The Millenium Institute for Fundamental and Applied Biology is financed in part by the Ministerio de Planificación y Cooperación (Chile).

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Authors and Affiliations

  1. Centro de Regulación Celular y Patología, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, MIFAB, Pontificia Universidad Católica de Chile, Santiago, Chile

    Valeria Mezzano, Daniel Cabrera, Cecilia Vial & Enrique Brandan

  2. Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Valeria Mezzano

  3. Department of Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, P.O. Box 114-D, Santiago, Chile

    Enrique Brandan

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  1. Valeria Mezzano
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  2. Daniel Cabrera
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  3. Cecilia Vial
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  4. Enrique Brandan
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Correspondence to Enrique Brandan.

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Mezzano, V., Cabrera, D., Vial, C. et al. Constitutively activated dystrophic muscle fibroblasts show a paradoxical response to TGF-β and CTGF/CCN2. J. Cell Commun. Signal. 1, 205–217 (2007). https://doi.org/10.1007/s12079-008-0018-2

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  • DOI: https://doi.org/10.1007/s12079-008-0018-2

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