Upregulation of chemokines and their receptors in duchenne muscular dystrophy: potential for attenuation of myofiber necrosis

Paepe, Boél De; Creus, Kim K.; Martin, Jean‐Jacques; Bleecker, Jan De

doi:10.1002/mus.23481

Cited by 47 publications

(51 citation statements)

References 32 publications

(31 reference statements)

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“…Muscle biopsies from children with Duchenne muscular dystrophy (DMD) showed increased CCL2 in the endothelium, and CCL2 has been implicated in macrophage and t-cell recruitment in the DMD mdx mouse model. [26, 27] It is possible these changes reflect physiological responses to inflammatory infiltrates in FSHD participant muscles, but further studies will be required to elucidate the exact relationship of circulating proteins to muscle inflammation.…”

Section: Discussionmentioning

confidence: 99%

Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy

Statland

Donlin-Smith

Tapscott

et al. 2014

Journal of Neuromuscular Diseases

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Background: Recent studies have proposed a unified genetic model for Facioscapulohumeral muscular dystrophy (FSHD), identifying potential therapeutic targets for future clinical trials. Serum biomarkers related to disease activity will be important for proof of concept or early phase clinical studies. Objective: To identify potential serum biomarkers in FSHD for possible use in future clinical trials. Methods: We performed a prospective cross-sectional study of serum biomarkers in 22 FSHD patients (19 FSHD1, 3 FSHD2) compared to 23 age and gender-matched healthy controls using a commercial multiplex, microsphere-based immune-fluorescent assay of 243 markers (Myriad, Human Discovery MAP 250, v2.0). Results: 169 markers had values sufficient for analysis. Correction for multiple testing identified 7 biomarkers below a 5% false discovery rate: creatine kinase MB fraction (CKMB, 6.52 fold change, P < 0.0001), tissue-type plasminogen activator (PLAT, 1.64 fold change, P < 0.0001), myoglobin (2.23 fold change, P = 0.0001), epidermal growth factor (EGF, 2.33 fold change, P = 0.0004), chemokine (C-C motif) ligand 2 (1.48 fold change, P = 0.0004), CD 40 ligand (1.89 fold change, P = 0.001), and vitronectin (VTN, 1.28 fold change, P = 0.001). Moderate correlations to measures of FSHD disease were seen for CKMB, PLAT, and EGF. Markers in the plasminogen pathway (PLAT and VTN) were correlated with each other in FSHD but not healthy controls. Conclusions: Commercial multiplex immune-fluorescent screening is a potentially powerful tool for identifying biomarkers for future FSHD therapeutic trials. Biomarkers identified in this study warrant further study in a larger prospective validation study.

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Section: Discussionmentioning

confidence: 99%

Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy

Statland

Donlin-Smith

Tapscott

et al. 2014

Journal of Neuromuscular Diseases

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“…Also, C-X-C motif chemokine ligands (CXCL) such as CXCL1, CXCL2, CXCL3, CXCL8, and CXCL11 for neutrophils contributing to the inflammatory phase during regeneration and absent from normal muscle fibers were induced in DMD myofibers 62. In addition, we found the secretion of macrophage migration inhibitory factor (MIF), an inflammatory cytokine and chemoattractant, was regulated by contraction in C2C12 myotubes 64.…”

Section: Potential Drugs Targeting Inflammatory Mechanisms In Dmdmentioning

confidence: 85%

“…We recently found that NF-κB is activated in C2C12 myotubes upon muscle contraction and upregulate C-C motif chemokine ligand (CCL) 2 secretion, inducing THP-1 monocyte chemoattraction 61. In addition, several CC chemokines including CCL2, which are the components of the largest family of chemokines, and chemoattractive for diverse inflammatory cells, showed increased expression in mdx muscle 62. These findings suggest that increased CCL2 secretion from DMD muscles may also contribute to monocyte chemoattraction into skeletal muscles.…”

Section: Potential Drugs Targeting Inflammatory Mechanisms In Dmdmentioning

confidence: 99%

“…MIF binds to the CXC chemokine receptors CXCR2 and CXCR4. CXCR2 is the receptor for CXCL1, 2, 3, and 8, which are the CXCLs upregulated in DMD muscles, and CXCR4 is the receptor for CXCL12, which is also upregulated in regenerating myofibers from DMD patients62 and thus can contribute to the inflammation. However, CXCL12 and CXCR4 may be difficult to use as candidates for anti-inflammation therapy because of their major role in muscle regeneration 66…”

Section: Potential Drugs Targeting Inflammatory Mechanisms In Dmdmentioning

confidence: 99%

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Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

Miyatake

Shimizu‐Motohashi

Takeda

et al. 2016

DDDT

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Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

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“…6 Chronic activation of signaling pathways involved in the inflammatory response further exacerbates dystrophic pathology by increasing myofiber expression of the major histocompatibility complex 18 and the secretion of chemokines and cytokines. 19 Although profibrotic signaling is initially activated in an attempt to repair compromised myofibers, it is susceptible to upregulation by the unremitting nature of muscle damage, which triggers fibrosis and perpetuates inflammation. 20 As the cellular mechanisms that govern these secondary responses are intimately linked, it is difficult to ascribe hierarchical order to the molecular events that exacerbate DMD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Recent advances in Duchenne muscular dystrophy

Perkins

Davies

2012

DNND

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Duchenne muscular dystrophy (DMD), an allelic X-linked progressive musclewasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene-and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene-and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.

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Upregulation of chemokines and their receptors in duchenne muscular dystrophy: potential for attenuation of myofiber necrosis

Abstract: Our data suggest a possible beneficial role for CXCR1/2/4 ligands in managing muscle fiber damage control and tissue regeneration. Upregulation of endothelial chemokine receptors and CXCL8, CCL2, and CCL5 expression by cytotoxic macrophages may regulate myofiber necrosis.

Cited by 47 publications

References 32 publications

Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy

Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy

Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

Recent advances in Duchenne muscular dystrophy

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