Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine.

Bernasconi, Pia; Torchiana, E; Confalonieri, Paolo; Brugnoni, Raffaella; Barresi, Rita; Mora, Marina; Cornelio, F.; Morandi, Lucia; Mantegazza, Renato

doi:10.1172/jci118101

Cited by 279 publications

(235 citation statements)

References 48 publications

(31 reference statements)

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“…In murine models of Leishmania amazonensis and Trypanosoma cruzi infection, TGF-␤ enhanced replication of either parasite both in vitro and in vivo (39)(40)(41)(42). Furthermore, there is strong evidence for a role for TGF-␤ in diseases characterized by accumulation of excess amounts of extracellular matrix such as mesangial injury in the rat model of glomerulonephritis (22), diabetic nephropathy in humans (43), cirrhosis of the liver both in rats and humans (38), and in muscular fibrosis seen in patients with Duchenne muscular dystrophy (44). Overproduction of TGF-␤ also has been linked to fibrotic pulmonary processes such as bleomycin-induced pulmonary fibrosis in rats (24,45), as well as lung pathology in humans with idiopathic pulmonary fibrosis (46) and sarcoidosis (47).…”

Section: Discussionmentioning

confidence: 99%

In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

Hirsch

Ellner

Blinkhorn

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

126

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We examined the capacity of the naturally occurring inhibitors of transforming growth factor ␤ (TGF-␤), decorin and latency associated peptide (LAP), to reverse depressed T cell functions in peripheral blood mononuclear cells (PBMCs) from patients with pulmonary tuberculosis (TB) in vitro and to counteract the suppressive properties of TGF-␤ on mycobacterial replication in blood monocytes (MN) in vitro. T cell blastogenesis in response to purified protein derivative (PPD) in PBMCs of TB patients that were cocultured with decorin or LAP reached levels comparable to those observed in healthy tuberculin-responsive control subjects. Decorin and LAP were as effective as neutralizing antibody to TGF-␤ in correcting depressed T cell proliferation. Coculture of PBMCs from healthy PPD reactive individuals with neutralizing antibody to TGF-␤, decorin, or LAP did not affect T cell blastogenesis. Levels of interferon-␥ in cultures of PPDstimulated PBMCs from patients with TB increased by more than 2-fold in the presence of maximal concentrations of either of the inhibitors of TGF-␤, whereas TGF-␤ immunoreactivity declined to background levels. Coculture with optimal concentrations of decorin or LAP also led to reductions in mycobacterial growth in MN infected with Mycobacterium tuberculosis (MTB) in vitro by 51% and 62%, respectively, when compared with cells left untreated. In parallel, levels of immunoreactive TGF-␤ in MTB-infected MN cultures containing decorin or LAP decreased to background levels. These data indicate that the naturally occurring inhibitors of TGF-␤, decorin and LAP, efficiently abrogate the suppressive effects of TGF-␤ in PBMCs of TB patients and in MN infected with MTB in vitro. Therefore, these agents may be considered as adjuncts to antituberculous chemotherapy, and may be particularly useful in treatment of TB that is unresponsive to conventional chemotherapy.

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Section: Discussionmentioning

confidence: 99%

In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

Hirsch

Ellner

Blinkhorn

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

126

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“…Increased TGF-β signaling has been observed in muscular dystrophy (11). Moreover, inhibition of TGF-β signaling improves muscle pathology and function in the mdx mouse model of muscular dystrophy (12).…”

Section: F 2 Mice Display An Intermediate Phenotype Between the Two Pmentioning

confidence: 99%

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Heydemann¹,

Ceco²,

Lim³

et al. 2009

J. Clin. Invest.

182

240

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Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β-binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β-binding protein that sequesters TGF-β and regulates its availability for binding to the TGF-β receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-β signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-β signaling and modify outcomes in muscular dystrophy.

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“…TGF-β1 has been previously shown to be upregulated in dystrophic muscle, likely playing a role in the initiation of the fibrotic cascade (27)(28)(29). TGF-β1 is a known profibrotic cytokine that downregulates miR-29c and is responsible for conversion of myoblasts to myofibroblasts, with an increase in collagen and muscle fibrogenesis (9).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin

Heller

Mendell

et al. 2017

JCI Insight

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Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine.

Cited by 279 publications

References 48 publications

In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

In vitrorestoration of T cell responses in tuberculosis and augmentation of monocyte effector function againstMycobacterium tuberculosisby natural inhibitors of transforming growth factor β

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin

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