Denervation-induced skeletal muscle fibrosis is mediated by CTGF/CCN2 independently of TGF-β.

Autor: Rebolledo DL; Centro de Envejecimiento y Regeneración, CARE Chile UC, Chile; Escuela de Obstetricia y Puericultura, Facultad de Salud, Universidad Bernardo O Higgins, Santiago, Chile. Electronic address: drebolledo@bio.puc.cl., González D; Centro de Envejecimiento y Regeneración, CARE Chile UC, Chile; Departamento de Biología Celular y Molecular, Chile. Electronic address: dsgonzalez@uc.cl., Faundez-Contreras J; Centro de Envejecimiento y Regeneración, CARE Chile UC, Chile; Departamento de Biología Celular y Molecular, Chile. Electronic address: jvfaundez@uc.cl., Contreras O; Centro de Envejecimiento y Regeneración, CARE Chile UC, Chile; Departamento de Biología Celular y Molecular, Chile. Electronic address: oicontre@uc.cl., Vio CP; Centro de Envejecimiento y Regeneración, CARE Chile UC, Chile; Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address: cvio@uc.cl., Murphy-Ullrich JE; Departments of Pathology, Cell Developmental and Integrative Biology, and Ophthalmology, The University of Alabama at Birmingham, AL, USA.. Electronic address: jmurphy@uabmc.edu., Lipson KE; FibroGen Inc., San Francisco, CA, USA. Electronic address: klipson@FibroGen.com., Brandan E; Centro de Envejecimiento y Regeneración, CARE Chile UC, Chile; Departamento de Biología Celular y Molecular, Chile. Electronic address: ebrandan@bio.puc.cl.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2019 Sep; Vol. 82, pp. 20-37. Date of Electronic Publication: 2019 Feb 01.
DOI: 10.1016/j.matbio.2019.01.002
Abstrakt: Muscular fibrosis is caused by excessive accumulation of extracellular matrix (ECM) that replaces functional tissue, and it is a feature of several myopathies and neuropathies. Knowledge of the biology and regulation of pro-fibrotic factors is critical for the development of new therapeutic strategies. Upon unilateral sciatic nerve transection, we observed accumulation of ECM proteins such as collagen and fibronectin in the denervated hindlimb, together with increased levels of the profibrotic factors transforming growth factor type β (TGF-β) and connective tissue growth factor (CTGF/CCN2). In mice hemizygous for CTGF/CCN2 or in mice treated with a blocking antibody against CTGF/CCN2, we observed reduced accumulation of ECM proteins after denervation as compared to control mice, with no changes in fibro/adipogenic progenitors (FAPs), suggesting a direct role of CTGF/CCN2 on denervation-induced fibrosis. During time course experiments, we observed that ECM proteins and CTGF/CCN2 levels are increased early after denervation (2-4 days), while TGF-β signaling shows a delayed kinetics of appearance (1-2 weeks). Furthermore, blockade of TGF-β signaling does not decrease fibronectin or CTGF levels after 4 days of denervation. These results suggest that in our model CTGF/CCN2 is not up-regulated by canonical TGF-β signaling early after denervation and that other factors are likely involved in the early fibrotic response following skeletal muscle denervation.
(Copyright © 2019 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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