Latent Transforming Growth Factor-β-Binding Protein-4 Regulates Transforming Growth Factor-β1 Bioavailability for Activation by Fibrogenic Lung Fibroblasts in Response to Bleomycin

Zhou, Yong; Koli, Katri; Hagood, James S.; Miao, Mi; Mavalli, Mahendra D.; Rifkin, Daniel B.; Murphy-Ullrich, Joanne E.

doi:10.2353/ajpath.2009.080620

Cited by 25 publications

(41 citation statements)

References 57 publications

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“…Fibroblasts deficient for LTBP4 are impaired in their ability to activate TGF-β, consistent with a requirement of LTBP4 for normal TGF-β activation. In LTBP4-deficient fibroblasts, reexpression of LTBP4 restored TGF-β activation, and this activation depended on the presence of both the TGF-β-binding and matrix-binding domains (23).…”

Section: Discussionmentioning

confidence: 93%

“…We maintained the fibroblast cultures at confluence for 5 days, since this condition is shown to be associated with increased LTBP4 expression and deposition into the matrix (22). TGF-β signaling in this assay is dependent on the presence of intact LTBP4 (23). After exposure to TGF-β, fibroblasts from D2-Sgcg mice displayed significantly more SMAD2/3 phosphorylation than those from 129-Sgcg mice ( Figure 6A).…”

Section: Tgf-β Signaling Is Increased By Deletion Of 12 Amino Acids Imentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 93%

Section: Tgf-β Signaling Is Increased By Deletion Of 12 Amino Acids Imentioning

confidence: 99%

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

Heydemann¹,

Ceco²,

Lim³

et al. 2009

J. Clin. Invest.

182

240

View full text Add to dashboard Cite

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“…Thy-1(Ϫ) lung fibroblasts did not acquire Thy-1 expression with repeated passage. These established Thy-1(ϩ) and Thy-1(Ϫ) lung fibroblasts have been used in multiple published studies (18,24,27,29,41). Lung fibroblasts were cultured in F12K medium (Cellgro, Herndon, VA) containing 10% PBS.…”

Section: Methodsmentioning

confidence: 99%

“…Data from our previous studies showed that Thy-1(Ϫ) lung fibroblasts, but not Thy-1(ϩ) lung fibroblasts, activate latent TGF-␤ in response to fibrogenic stimuli (27). LTBP-4 mediates latent TGF-␤1 activation by Thy-1(Ϫ) lung fibroblasts in response to bleomycin (18). Despite these findings, the molecular mechanisms underlying Thy-1 regulation of lung fibroblast phenotype are not well understood.…”

mentioning

confidence: 96%

“…Most cells, including lung fibroblasts, secrete TGF-␤1 as a large latent complex (LLC) in which the SLC binds to a second gene product named latent TGF-␤-binding protein (LTBP) (10,11). LTBPs (LTBP-1, -3, and -4) target TGF-␤1 to the ECM and regulate latent TGF-␤1 activation (12)(13)(14)(15)(16)(17)(18). Latent TGF-␤1 activation can occur either through protease-dependent cleavage of LAP that releases the C-terminal active TGF-␤1 domain from the latent complex or by induction of a conformational change in the latent complex that exposes the active TGF-␤1 domain to allow binding to its cell surface receptors (19 -21).…”

mentioning

confidence: 99%

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Thy-1-Integrin αvβ5 Interactions Inhibit Lung Fibroblast Contraction-induced Latent Transforming Growth Factor-β1 Activation and Myofibroblast Differentiation

Zhou

Hagood

et al. 2010

Journal of Biological Chemistry

Self Cite

114

107

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Myofibroblasts, key effector cells in tissue fibrosis, are specialized contractile cells. Lung myofibroblast contraction induces integrin ␣ v ␤ 5 -dependent latent transforming growth factor (TGF)-␤1 activation suggests that myofibroblast contractility may be a driving force for the persistent myofibroblast differentiation observed in fibrotic lungs. Understanding the mechanisms that regulate fibroblast contraction and mechanotransduction will add new insights into the pathogenesis of lung fibrosis and may lead to new therapeutic approaches for treating fibrotic lung diseases. We and others previously demonstrated that lung fibroblast expression of Thy-1 prevents lung fibrosis. The mechanisms underlying the anti-fibrotic effect of Thy-1 are not well understood. In this study, we showed that Thy-1 interacts with integrin ␣ v ␤ 5 , both in a cell-free system and on the cell surface of rat lung fibroblasts. Thy-1-integrin ␣ v ␤ 5 interactions are RLDdependent because mutated Thy-1, in which RLD is replaced by RLE, loses the ability to bind the integrin. Furthermore, Thy-1 expression prevents fibroblast contraction-induced, integrin ␣ v ␤ 5 -dependent latent TGF-␤1 activation and TGF-␤1-dependent lung myofibroblast differentiation. In contrast, lack of Thy-1 expression or disruption of Thy-1-␣ v ␤ 5 interactions renders lung fibroblasts susceptible to contraction-induced latent TGF-␤1 activation and myofibroblast differentiation. These data suggest that Thy-1-integrin ␣ v ␤ 5 interactions inhibit contraction-induced latent TGF-␤1 activation, presumably by blocking the binding of extracellular matrix-bound latent TGF-␤1 with integrin ␣ v ␤ 5 . Our studies suggest that targeting key mechanotransducers to inhibit mechanotransduction might be an effective approach to inhibit the deleterious effects of myofibroblast contraction on lung fibrogenesis.

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LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy

Flanigan

Ceco

Lamar

et al. 2013

Annals of Neurology

205

251

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Objective Duchenne Muscular Dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-β binding protein 4, was previously discovered in a genomewide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort. Methods We analyzed nonsynonymous SNPs from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form “VTTT” and “IAAM” LTBP4 haplotypes. Results Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to TGFβ displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4's role as regulator of TGFβ. Interpretation LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients.

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Latent Transforming Growth Factor-β-Binding Protein-4 Regulates Transforming Growth Factor-β1 Bioavailability for Activation by Fibrogenic Lung Fibroblasts in Response to Bleomycin

Cited by 25 publications

References 57 publications

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

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

Thy-1-Integrin αvβ5 Interactions Inhibit Lung Fibroblast Contraction-induced Latent Transforming Growth Factor-β1 Activation and Myofibroblast Differentiation

LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy

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