Early onset of inflammation and later involvement of TGFβ in Duchenne muscular dystrophy

Chen, Y. W.; Nagaraju, Kanneboyina; Bakay, Marina; McIntyre, Orinthal; Rawat, Rashmi; Shi, Rongye; Hoffman, Eric P.

doi:10.1212/01.wnl.0000173836.09176.c4

Cited by 261 publications

(264 citation statements)

References 72 publications

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“…The majority of genetic mutations identified in patients with MD appear to affect the multiprotein sarcolemmal-spanning dystrophin-glycoprotein complex, which is critical for stabilization of the membrane and prevention of calcium overload, leading to myofiber death and an inflammatory response (2). One such inflammatory mediator, transforming growth factor (TGF)-β, is thought to worsen MD and lead to increased fibrosis in human dystrophic muscle (3,4) and animal models of dystrophy (5); for example, administration of decorin (a TGF-β antagonist) reduces collagen expression in the diaphragm of dystrophin-deficient mdx mice (6), and losartan (an angiotensin II type 1 receptor blocker thought to reduce TGF-β activity) normalizes muscle architecture and improves function in animal models of myopathy (7,8). Recently, genetic alterations in the TGF-β pathway, such as changes in latent TGF-β binding protein 4, also have supported the theory of a strong interplay between TGF-β-induced fibrosis and MD severity (9).…”

mentioning

confidence: 99%

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

Lorts

Schwanekamp

Baudino

et al. 2012

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

124

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The muscular dystrophies are broadly classified as muscle wasting diseases with myofiber dropout due to cellular necrosis, inflammation, alterations in extracellular matrix composition, and fatty cell replacement. These events transpire and progress despite ongoing myofiber regeneration from endogenous satellite cells. The degeneration/regeneration response to muscle injury/disease is modulated by the proinflammatory cytokine transforming growth factor-β (TGF-β), which can also profoundly influence extracellular matrix composition through increased secretion of profibrotic proteins, such as the matricellular protein periostin. Here we show that up-regulation and secretion of periostin is pathological and enhances disease in the δ-sarcoglycan null ( Sgcd −/− ) mouse model of muscular dystrophy (MD). Indeed, MD mice lacking the Postn gene showed dramatic improvement in skeletal muscle structure and function. Mechanistically, Postn gene deletion altered TGF-β signaling so that it now enhanced tissue regeneration with reduced levels of fibrosis. Systemic antagonism of TGF-β with a neutralizing monoclonal antibody mitigated the beneficial effects of Postn deletion in vivo. These data suggest that periostin functions as a disease determinant in MD by promoting/allowing the pathological effects of TGF-β, suggesting that inhibition of periostin could represent a unique treatment approach.

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mentioning

confidence: 99%

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

Lorts

Schwanekamp

Baudino

et al. 2012

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

124

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“…86,87 NF-B signaling is persistently elevated in immune cells, as well as regenerating muscle fibers in mdx muscle, 88 and evidence exists that this same pathway is also active in DMD patients. 81,88,89 Pharmacological inhibition of I B kinase (IKK), a direct upstream positive regulator of NF-B, resulted in improved pathology and muscle function in mdx mice. 88 Activators of NF-B, such as TNF-␣ are upregulated in DMD muscle.…”

Section: Emerging Therapeutic Targetsmentioning

confidence: 99%

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Wagner

2008

Neurotherapeutics

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Summary:Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy. The cornerstones of current treatment include corticosteroids for skeletal muscle weakness, afterload reduction for cardiomyopathy, and noninvasive ventilation for respiratory failure. With these interventions, patients are walking and living longer. However, the current status is still far from adequate. Increased private and federal funding of studies in Duchenne muscular dystrophy has led to a large number of novel agents with propitious therapeutic potential. These include agents that modify dystrophin expression, increase muscle growth and regeneration, and modulate inflammatory responses. Many of these agents are already in clinical trials. Challenges to the development of additional novel therapeutics exist, including lack of validated animal models and lack of adequate biomarkers as surrogate endpoints. However, these challenges are not insurmountable and the next decade will likely see meaningful, new treatment options introduced into the clinical care of patients with Duchenne muscular dystrophy.

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“…Current available large-scale parallel gene expression analysis has provided greater ease for investigating the underlying molecular pathophysiological mechanisms of DMD. Several gene expression profiling studies (Chen et al, 2000;2005;Haslett et al, 2002;Pescatori et al, 2007;Wong et al, 2009) have been carried out, providing insights into the pathology of DMD. These studies typically implemented standard analysis of variance/regression to identify the differentially expressed genes over two types of samples.…”

Section: Introductionmentioning

confidence: 99%

Partial least squares based identification of Duchenne muscular dystrophy specific genes

An¹,

Zheng²,

Zhang³

et al. 2013

J. Zhejiang Univ. Sci. B

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Large-scale parallel gene expression analysis has provided a greater ease for investigating the underlying mechanisms of Duchenne muscular dystrophy (DMD). Previous studies typically implemented variance/regression analysis, which would be fundamentally flawed when unaccounted sources of variability in the arrays existed. Here we aim to identify genes that contribute to the pathology of DMD using partial least squares (PLS) based analysis. We carried out PLS-based analysis with two datasets downloaded from the Gene Expression Omnibus (GEO) database to identify genes contributing to the pathology of DMD. Except for the genes related to inflammation, muscle regeneration and extracellular matrix (ECM) modeling, we found some genes with high fold change, which have not been identified by previous studies, such as SRPX, GPNMB, SAT1, and LYZ. In addition, downregulation of the fatty acid metabolism pathway was found, which may be related to the progressive muscle wasting process. Our results provide a better understanding for the downstream mechanisms of DMD.

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Early onset of inflammation and later involvement of TGFβ in Duchenne muscular dystrophy

Abstract: Our data show stage-specific remodeling of human dystrophin-deficient muscle, with inflammatory pathways predominating in the presymptomatic stages and acute activation of TGFbeta and failure of metabolic pathways later in the disease.

Cited by 261 publications

References 72 publications

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Partial least squares based identification of Duchenne muscular dystrophy specific genes

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