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Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin. Prior work has shown that DMD progression can vary, depending on the genetic makeup of the patient. Several modifier alleles have been identified including LTBP4 and SPP1. We previously showed that Spp1 exacerbates the DMD phenotype in the mdx mouse model by promoting fibrosis and by skewing macrophage polarization. Here, we studied the mechanisms involved in Spp1's promotion of fibrosis by using both isolated fibroblasts and genetically modified mice. We found that Spp1 upregulates collagen expression in mdx fibroblasts by enhancing TGFβ signaling. Spp1's effects on TGFβ signaling are through induction of MMP9 expression. MMP9 is a protease that can release active TGFβ ligand from its latent complex. In support for activation of this pathway in our model, we showed that treatment of mdx fibroblasts with MMP9 inhibitor led to accumulation of the TGFβ latent complex, decreased levels of active TGFβ and reduced collagen expression. Correspondingly, we found reduced active TGFβ in Spp1-/-mdxB10 and Mmp9-/-mdxB10 muscles in vivo. Taken together with previous observations of reduced fibrosis in both models, these data suggest that Spp1 acts upstream of TGFβ to promote fibrosis in mdx muscles. We found that in the context of constitutively upregulated TGFβ signaling (such as in the mdxD2 model), ablation of Spp1 has very little effect on fibrosis. Finally, we performed proof-of-concept studies showing that postnatal pharmacological inhibition of Spp1 reduces fibrosis and improves muscle function in mdx mice.
This article was published in the following journal.
Name: Human molecular genetics
Eccentric contractions (ECC) induce force loss in several skeletal muscles of dystrophin-deficient mice (mdx), with the exception of the soleus (Sol). The eccentric force:isometric force (ECC:ISO), ex...
Progressive muscle injury and weakness are hallmarks of Duchenne muscular dystrophy. We showed previously that quercetin (Q) partially protected dystrophic limb muscles from disease-related injury. As...
Mechanical forces regulate muscle development, hypertrophy, and homeostasis. Force-transmitting structures allow mechanotransduction at the sarcolemma, cytoskeleton, and nuclear envelope. There is gro...
Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) is a promising treatment strategy for Duchenne muscular dystrophy (DMD). The most significant limitation of these clinically used com...
A Phase 2 clinical pharmacology study to assess dystrophin levels in ambulatory nmDMD subjects before and after treatment with ataluren for 40 weeks using a quantitative dystrophin assay, ...
The proposed phase I clinical trial is a pilot study to evaluate safety and biological activity of the rAAVrh74.MCK.micro-Dystrophin vector administered by an intramuscular route. This st...
This study is designed to generate additional data on the effect of ataluren for producing dystrophin protein in nonsense mutation nmDMD participants. This study will evaluate dystrophin l...
Fibroblasts can be cultured from human skin biopsies using fetal bovine serum and artificial growth medium. Fibroblasts cultured in this way retain the genetic characteristics of their do...
The purpose of this study is to determine the safety of a miniature dystrophin gene in the treatment of progressive muscle weakness due to Duchenne Muscular Dystrophy (DMD).
Dystrophin-associated proteins that play role in the formation of a transmembrane link between laminin-2 and DYSTROPHIN. Both the alpha and the beta subtypes of dystroglycan originate via POST-TRANSLATIONAL PROTEIN PROCESSING of a single precursor protein.
A group of proteins that associate with DYSTROPHIN at the CELL MEMBRANE to form the DYSTROPHIN-ASSOCIATED PROTEIN COMPLEX.
A macromolecular complex of proteins that includes DYSTROPHIN and DYSTROPHIN-ASSOCIATED PROTEINS. It plays a structural role in the linking the CYTOSKELETON to the EXTRACELLULAR MATRIX.
A negatively-charged extracellular matrix protein that plays a role in the regulation of BONE metabolism and a variety of other biological functions. Cell signaling by osteopontin may occur through a cell adhesion sequence that recognizes INTEGRIN ALPHA-V BETA-3.
A relatively large mass of unusually firm scarlike connective tissue resulting from active participation of fibroblasts, occurring most frequently in the abdominal muscles of women who have borne children. The fibroblasts infiltrate surrounding muscle and fascia. (Stedman, 25th ed)
Muscular dystrophy is a group of degenerative inherited disorders causing muscle weakness and loss of muscle tissue. The different types are Becker muscular dystrophy, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, Facioscapulohumeral mu...
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...