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A comparison of the bone and growth phenotype of mdx, mdx:Cmah^-/- and mdx:Utrn ^+/- murine models with the C57BL/10 wild-type mouse.

ABSTRACT: The muscular dystrophy X-linked (mdx) mouse is commonly used as a mouse model of Duchenne muscular dystrophy (DMD). Its phenotype is, however, mild, and other mouse models have been explored. The mdx:Cmah^-/- mouse carries a human-like mutation in the Cmah gene and has a severe muscle phenotype, but its growth and bone development are unknown. In this study, we compared male mdx, mdx:Utrn ^+/-, mdx:Cmah^-/- and wild-type (WT) mice at 3, 5 and 7 weeks of age to determine the suitability of the mdx:Cmah^-/- mouse as a model for assessing growth and skeletal development in DMD. The m dx:Cmah^-/- mice were lighter than WT mice at 3 weeks, but heavier at 7 weeks, and showed an increased growth rate at 5 weeks. Cortical bone fraction as assessed by micro-computed tomography was greater in both mdx and mdx: C mah^-/- mice versus WT mice at 7 weeks. Tissue mineral density was also higher in mdx:Cmah^-/- mice at 3 and 7 weeks. Gene profiling of mdx:Cmah^-/- bone identified increased expression of Igf1, Igf1r and Vegfa Both the mdx and mdx:Cmah^-/- mice showed an increased proportion of regulated bone marrow adipose tissue (BMAT) but a reduction in constitutive BMAT. The mdx:Cmah^-/- mice show evidence of catch-up growth and more rapid bone development. This pattern does not mimic the typical DMD growth trajectory and therefore the utility of the mdx:Cmah^-/- mouse for studying growth and skeletal development in DMD is limited. Further studies of this model may, however, shed light on the phenomenon of catch-up growth.This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Wood CL

PROVIDER: S-EPMC6994935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cardiac failure is a major cause of mortality in patients with Duchenne muscular dystrophy (DMD). Antisense-mediated exon skipping has the ability to correct out-of-frame mutations in DMD to produce truncated but functional dystrophin. Traditional antisense approaches have however been limited by their poor uptake into cardiac muscle. The addition of cell-penetrating peptides to antisense molecules has increased their potency and improved their uptake into all muscles, including the heart. We have investigated the efficacy of the Peptide-conjugated phosphodiamidate morpholino oligomer (P-PMO) Pip6a-PMO, for restoration of cardiac dystrophin and functional rescue in DMD mice- the mdx mouse and the less well characterised Cmah-/-mdx mouse (which carry a human-like mutation in the mouse Cmah gene as well as a mutation in DMD). In our first study male mdx mice were administered Pip6a-PMO, i.v, fortnightly from 12 to 30 weeks of age alongside mock-injected age-matched mdx and C57BL10 controls. Mice received 4 doses of 18 mg/kg followed by 8 doses of 12.5 mg/kg. The cardiac function of the mice was analysed 2 weeks after their final injection by MRI followed by conductance catheter and their muscles were harvested for dystrophin quantification. In the second study, male Cmah-/-mdx mice, received 12.5 mg/kg Pip6a-PMO, i.v fortnightly from 8 to 26 weeks and assessed by MRI at 3 time points (12, 18 and 28 weeks) alongside mock-injected age-matched mdx, C57BL10 and Cmah-/-mdx controls. The mice also underwent MEMRI and conductance catheter at 28 weeks. This allowed us to characterise the cardiac phenotype of Cmah-/-mdx mice as well as assess the effects of P-PMO on cardiac function. Pip6a-PMO treatment resulted in significant restoration of dystrophin in mdx and Cmah-/-mdx mice (37.5% and 51.6%, respectively), which was sufficient to significantly improve cardiac function, ameliorating both right and left ventricular dysfunction. Cmah-/-mdx mice showed an abnormal response to dobutamine stress test and this was completely ameliorated by PIP6a-PMO treatment. These encouraging data suggest that total restoration of dystrophin may not be required to significantly improve cardiac outcome in DMD patients and that it may be realistic to expect functional improvements with modest levels of dystrophin restoration which may be very achievable in future clinical trials.

Project description:BackgroundPeriodontitis is characterized by progressive inflammation and alveolar bone loss resulting in tooth loss finally. Macrophages including pro-inflammatory M1-like macrophages and reparative M2-like macrophages play a vital role in inflammation and tissue homeostasis in periodontitis. Among them, reparative M2-like macrophages have been shown to promote tissue repair and prevent bone loss. However, the mechanism of reparative M2 macrophages-induced osteoprotective effect remains elusive.ResultsExosomes from reparative M2-like macrophages (M2-Exos) were isolated and identified successfully. M2-Exos could promote bone marrow stromal cells (BMSCs) osteogenic differentiation while suppressing bone marrow derived macrophage (BMDM) osteoclast formation, and prohibit pathological alveolar bone resorption because of the intercellular communication via exosomes. High expression level of IL-10 mRNA was detected not only in reparative M2-like macrophages but also in M2-Exos. Meanwhile, IL-10 expression level in BMSCs or BMDM was also upregulated significantly after co-culturing with M2-Exos in a concentration-dependent manner. In vitro, recombinant IL-10 proteins had the ability to selectively promote osteogenic differentiation of BMSCs and hinder osteoclast differentiation of BMDM. Moreover, after treatment with M2-Exos and IL-10R antibody together, the capacity of promoting osteogenesis and suppressing osteoclastogenesis of M2-Exos was significantly reversed. In vivo experiments further showed that M2-Exos reduced alveolar bone resorption in mice with periodontitis via IL-10/IL-10R pathway.ConclusionIn conclusion, our results demonstrate that the reparative M2-like macrophages could promote osteogenesis while inhibiting osteoclastogenesis in vitro as well as protect alveolar bone against resorption in vivo significantly. M2-Exos could upregulate the IL-10 cytokines expression of BMSCs and BMDM via delivering exosomal IL-10 mRNA to cells directly, leading to activation of the cellular IL-10/IL-10R pathway to regulate cells differentiation and bone metabolism. These results might partly account for the mechanism of osteoprotective effect of reparative M2-like macrophages and provide a novel perspective and a potential therapeutic approach on improving alveolar resorption by M2-Exos.

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A comparison of the bone and growth phenotype of mdx, mdx:Cmah^-/- and mdx:Utrn ^+/- murine models with the C57BL/10 wild-type mouse.

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Dataset Information

A comparison of the bone and growth phenotype of mdx, mdx:Cmah-/- and mdx:Utrn +/- murine models with the C57BL/10 wild-type mouse.

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OmicsDI is part of the ELIXIR infrastructure

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A comparison of the bone and growth phenotype of mdx, mdx:Cmah^-/- and mdx:Utrn ^+/- murine models with the C57BL/10 wild-type mouse.