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Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans.

ABSTRACT: Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro-computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-?A, and TGF?2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients.

SUBMITTER: Rufo A

PROVIDER: S-EPMC3150693 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans.

Rufo Anna A Del Fattore Andrea A Capulli Mattia M Carvello Francesco F De Pasquale Loredana L Ferrari Serge S Pierroz Dominique D Morandi Lucia L De Simone Michele M Rucci Nadia N Bertini Enrico E Bianchi Maria Luisa ML De Benedetti Fabrizio F Teti Anna A

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20110801 8

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro-computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated i ...[more]

PMID: 21509823

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Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Project description:BackgroundFibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the 'easy-to-access' limb muscles, thus precluding fibrosis research and the testing of novel therapies.MethodsWe developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice.ResultsThese strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma.ConclusionsWe have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis-driven dystrophy progression and aberrant regeneration.

Project description:BackgroundDuchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder with its primary insult on the skeletal muscle. Severe muscle wasting, chronic inflammation and fibrosis characterize dystrophic muscle. Here we identify dysregulated pathways in DMD utilizing a co-expression network approach as described in Weighted Gene Co-expression Network Analysis (WGCNA). Specifically, we utilize WGCNA's "preservation" statistics to identify gene modules that exhibit a weak conservation of network topology within healthy and dystrophic networks. Preservation statistics rank modules based on their topological metrics such as node density, connectivity and separability between networks.MethodsRaw data for DMD was downloaded from Gene Expression Omnibus (GSE6011) and suitably preprocessed. Co-expression networks for each condition (healthy and dystrophic) were generated using the WGCNA library in R. Preservation of healthy network edges was evaluated with respect to dystrophic muscle and vice versa using WGCNA. Highly exclusive gene pairs for each of the low preserved modules within both networks were also determined using a specificity measure.ResultsA total of 11 and 10 co-expressed modules were identified in the networks generated from 13 healthy and 23 dystrophic samples respectively. 5 out of the 11, and 4 out of the 10 modules were identified as exhibiting none-to-weak preservation. Functional enrichment analysis identified that these weakly preserved modules were highly relevant to the condition under study. For instance, weakly preserved dystrophic module D2 exhibited the highest fraction of genes exclusive to DMD. The highly specific gene pairs identified within these modules were enriched for genes activated in response to wounding and affect the extracellular matrix including several markers such as SPP1, MMP9 and ITGB2.ConclusionThe proposed approach allowed us to identify clusters of genes that are non-randomly associated with the disease. Furthermore, highly specific gene pairs pointed to interactions between known markers of disease and identification of putative markers likely associated with disease. The analysis also helped identify putative novel interactions associated with the progression of DMD.

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Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans.

Publications

Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans.

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