| 1. |
- Gustafsson, Renata, et al.
(författare)
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Gene expression profiling of differentiating embryonic stem cells expressing dominant negative fibroblast growth factor receptor 2.
- 2007
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Ingår i: Matrix Biology. - : Elsevier BV. - 1569-1802 .- 0945-053X. ; 26, s. 197-205
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic stein (ES) cells are derived from the inner cell mass of the blastocyst and can be cultured as three-dimensional embryoid bodies (EBs) in which embryonic pregastrulation stages are faithfully mimicked. Fibroblast growth factor receptors (mainly FGFR2) are involved in the first differentiation events during early mammalian embryogenesis. It has been demonstrated that the presence of FGFR2 is a prerequisite for laminin-111 and collagen type IV synthesis and subsequently basement membrane formation in EBs. To identify genes that are influenced by FGFR signalling, we performed global gene expression profiling of differentiating EBs expressing dominant negative FGFR2 (dnFGFR2), acquiring an extensive catalogue of down- and up-regulated genes. We show a strong down-regulation of endodermal and basement membrane related genes, which strengthen the view that the FGFR signalling pathway is a main stimulator of basement membrane synthesis in EBs. We further present down-regulation of genes previously not linked to FGFR signalling, and in addition an active transcription of some mesodermal related genes in differentiating dnFGFR2 EBs.
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| 2. |
- Olsson, Magnus, et al.
(författare)
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Nulp1, a novel basic helix-loop-helix protein expressed broadly during early embryonic organogenesis and prominently in developing dorsal root ganglia.
- 2002
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 308:3, s. 361-370
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Tidskriftsartikel (refereegranskat)abstract
- The basic helix-loop-helix (bHLH) proteins control differentiation and development of a variety of organs. We have isolated the complementary DNA (cDNA) of a novel class of bHLH transcription factors. The previously uncharacterized bHLH messenger RNA (mRNA) was identified by RNA fingerprinting by comparing embryonic and adult mRNA. The reading frame sequence predicts a new class of bHLH family. Northern blotting of embryonic stages demonstrated a 3.2-kb transcript present in several embryonic tissues, including kidney, brain, heart, and lung, in a fashion confirmatory with the RNA-fingerprinting data. In situ hybridization of cryosections detected strong signals in the dorsal root ganglia of 14-day-old mouse embryos (E14). Transient transfection of human embryonic kidney cells with Nulp1-EGFP demonstrated nuclear localization. The complex expression pattern and unique protein sequence, including an acidic amino terminal and putative transcription activation domain, suggests that Nulp1 may have a distinct role in embryonic development of many organs, including the adult brain.
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| 3. |
- Agrawal, Smriti, et al.
(författare)
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Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis.
- 2006
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 203:4, s. 1007-1019
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Tidskriftsartikel (refereegranskat)abstract
- The endothelial cell monolayer of cerebral vessels and its basement membrane (BM) are ensheathed by the astrocyte endfeet, the leptomeningeal cells, and their associated parenchymal BM, all of which contribute to establishment of the blood–brain barrier (BBB). As a consequence of this unique structure, leukocyte penetration of cerebral vessels is a multistep event. In mouse experimental autoimmune encephalomyelitis (EAE), a widely used central nervous system inflammatory model, leukocytes first penetrate the endothelial cell monolayer and underlying BM using integrin β1-mediated processes, but mechanisms used to penetrate the second barrier defined by the parenchymal BM and glia limitans remain uninvestigated. We show here that macrophage-derived gelatinase (matrix metalloproteinase [MMP]-2 and MMP-9) activity is crucial for leukocyte penetration of the parenchymal BM. Dystroglycan, a transmembrane receptor that anchors astrocyte endfeet to the parenchymal BM via high affinity interactions with laminins 1 and 2, perlecan and agrin, is identified as a specific substrate of MMP-2 and MMP-9. Ablation of both MMP-2 and MMP-9 in double knockout mice confers resistance to EAE by inhibiting dystroglycan cleavage and preventing leukocyte infiltration. This is the first description of selective in situ proteolytic damage of a BBB-specific molecule at sites of leukocyte infiltration.
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| 4. |
- Carmignac, Virginie, et al.
(författare)
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Autophagy is increased in laminin {alpha}2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A.
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:24, s. 4891-4902
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Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy caused by laminin α2 chain deficiency (also known as MDC1A) is a severe and incapacitating disease, characterized by massive muscle wasting. The ubiquitin-proteasome system plays a major role in muscle wasting and we recently demonstrated that increased proteasomal activity is a feature of MDC1A. The autophagy-lysosome pathway is the other major system involved in degradation of proteins and organelles within the muscle cell. However, it remains to be determined if the autophagy-lysosome pathway is dysregulated in muscular dystrophies, including MDC1A. Using the dy(3K)/dy(3K) mouse model of laminin α2 chain deficiency and MDC1A patient muscle, we show here that expression of autophagy-related genes is upregulated in laminin α2 chain-deficient muscle. Moreover, we found that autophagy inhibition significantly improves the dystrophic dy(3K)/dy(3K) phenotype. In particular, we show that systemic injection of 3-methyladenine (3-MA) reduces muscle fibrosis, atrophy, apoptosis and increases muscle regeneration and muscle mass. Importantly, lifespan and locomotive behavior were also greatly improved. These findings indicate that enhanced autophagic activity is pathogenic and that autophagy inhibition holds a promising therapeutic potential in the treatment of MDC1A.
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| 5. |
- Carmignac, Virginie, et al.
(författare)
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Cell-matrix interactions in muscle disease.
- 2012
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417. ; 226, s. 200-218
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix provides a solid scaffold and signals to cells through extracellular matrix receptors. The cell-matrix interactions are crucial for normal biological processes and when disrupted they may lead to pathological processes. In particular, the biological importance of extracellular matrix-cell membrane-cytoskeleton interactions in skeletal muscle is accentuated by the number of inherited muscle diseases caused by mutations in proteins conferring these interactions. In this review we will introduce laminins, collagens, dystroglycan, integrins, dystrophin and sarcoglycans. Mutations in corresponding genes cause various forms of muscular dystrophy. The muscle disorders will be presented as well as advances toward development of treatment. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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| 6. |
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| 7. |
- Carmignac, Virginie, et al.
(författare)
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Proteasome Inhibition Improves the Muscle of Laminin {alpha}2 Chain Deficient Mice.
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:3, s. 541-552
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Tidskriftsartikel (refereegranskat)abstract
- Muscle atrophy, a significant characteristic of congenital muscular dystrophy with laminin α2 chain deficiency (also known as MDC1A), occurs by a change in the normal balance between protein synthesis and protein degradation. The ubiquitin-proteasome system plays a key role in protein degradation in skeletal muscle cells. In order to identify new targets for drug therapy against MDC1A, we have investigated whether increased proteasomal degradation is a feature of MDC1A. Using the generated dy(3K)/dy(3K) mutant mouse model of MDC1A, we studied the expression of members of the ubiquitin-proteasome pathway in laminin α2 chain deficient muscle and we treated dy(3K)/dy(3K) mice with the proteasome inhibitor MG-132. We show that members of the ubiquitin-proteasome system are upregulated and that the global ubiquitination of proteins is raised in dystrophic limb muscles. Also, phosphorylation of Akt is diminished in diseased muscles. Importantly, proteasome inhibition significantly improves the dystrophic dy(3K)/dy(3K) phenotype. Specifically, treatment with MG-132 increases lifespan, enhances locomotive activity, enlarges muscle fiber diameter, reduces fibrosis, restores Akt phosphorylation and decreases apoptosis. These studies promote better understanding of the disease process in mice and could lead to a drug therapy for MDC1A patients.
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| 8. |
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| 9. |
- Durbeej-Hjalt, Madeleine
(författare)
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Laminin-α2 Chain-Deficient Congenital Muscular Dystrophy: Pathophysiology and Development of Treatment.
- 2015
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Ingår i: Current Topics in Membranes. - : Elsevier. - 1063-5823. ; 76, s. 31-60
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Tidskriftsartikel (refereegranskat)abstract
- Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the α2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life-threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties. Several adequate animal models for laminin-α2 chain deficiency exist and analyses of different MDC1A mouse models have led to a significant improvement in our understanding of MDC1A pathogenesis. Importantly, the animal models have been indispensable tools for the preclinical development of new therapeutic approaches for laminin-α2 chain deficiency, highlighting a number of important disease driving mechanisms that can be targeted by pharmacological approaches. In this chapter, I will describe laminin-211 and discuss the cellular and molecular pathophysiology of MDC1A as well as progression toward development of treatment.
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| 10. |
- Durbeej-Hjalt, Madeleine
(författare)
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Laminins.
- 2010
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 339, s. 259-268
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Tidskriftsartikel (refereegranskat)abstract
- Laminins are cell adhesion molecules that comprise a family of glycoproteins found predominantly in basement membranes, which are the thin sheets of extracellular matrix that underlie epithelial and endothelial cells and surround muscle cells, Schwann cells, and fat cells. Many laminins self-assemble to form networks that remain in close association with cells through interactions with cell surface receptors. Laminins are vital for many physiological functions. They are essential for early embryonic development and organogenesis and have crucial functions in several tissues including muscle, nerve, skin, kidney, lung, and the vasculature. A great wealth of data on laminins is available, and an in-depth description is not attempted here. In this review, I will instead provide a snapshot of laminin structure, tissue distribution, and interactions with other matrix molecules and receptors and briefly describe laminin mutations in mice and humans. Several illuminating and timely reviews are cited that can be consulted for references to original articles and more detailed information concerning laminins.
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| 11. |
- Elowsson, Linda, et al.
(författare)
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Evaluation of macroporous blood and plasma scaffolds for skeletal muscle tissue engineering
- 2013
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Ingår i: Biomaterials Science. - : Royal Society of Chemistry (RSC). - 2047-4830 .- 2047-4849. ; 1:4, s. 402-410
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Tidskriftsartikel (refereegranskat)abstract
- The field of tissue engineering has a growing need for suitable scaffold materials to become attractive as a clinical therapy. To use a completely autologous construct to repair a damaged or diseased tissue is an appealing thought. As a model system, two types of scaffolds were prepared from biological fluids: blood and plasma. The prepared scaffolds formed a macroporous structure with elastic mechanical properties that were further evaluated with myoblast cell line (C2C12) cultivation and transplantation into mouse skeletal muscle. The cells were found to attach, proliferate, and migrate through all the different scaffolds. Moreover, the cells underwent myogenic differentiation, showing typical cell morphology aligned in a parallel fashion. An increased level of myogenin mRNA was found with the time of culture. Furthermore, myogenic markers MyoD1, desmin, myogenin and myosin, as well as beta-dystroglycan and the laminin alpha 2 chain, were found to be expressed. In vivo data indicated that the scaffolds degraded and were replaced with regenerated muscle fibres. We conclude that the two types of macroporous scaffolds based on blood or plasma have potential in the field of skeletal muscle tissue engineering.
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| 12. |
- Elowsson, Linda, et al.
(författare)
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Porous protein-based scaffolds prepared through freezing as potential scaffolds for tissue engineering.
- 2012
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Ingår i: Journal of Materials Science: Materials in Medicine. - : Springer Science and Business Media LLC. - 1573-4838 .- 0957-4530. ; 23:10, s. 2489-2498
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Tidskriftsartikel (refereegranskat)abstract
- Successful tissue engineering with the aid of a polymer scaffold offers the possibility to produce a larger construct and to mould the shape after the defect. We investigated the use of cryogelation to form protein-based scaffolds through different types of formation mechanisms; enzymatic crosslinking, chemical crosslinking, and non-covalent interactions. Casein was found to best suited for enzymatic crosslinking, gelatin for chemical crosslinking, and ovalbumin for non-covalent interactions. Fibroblasts and myoblasts were used to evaluate the cryogels for tissue engineering purposes. The stability of the cryogels over time in culture differed depending on formation mechanism. Casein cryogels showed best potential to be used in skeletal tissue engineering, whereas gelatin cryogels would be more suitable for compliable soft tissues even though it also seemed to support a myogenic phenotype. Ovalbumin cryogels would be better suited for elastic tissues with faster regeneration properties due to its faster degradation time. Overall, the cryogelation technique offers a fast, cheap and reproducible way of creating porous scaffolds from proteins without the use of toxic compounds.
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| 13. |
- Fontes Oliveira, Cibely, et al.
(författare)
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Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322.
-
Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD. Here, we have investigated whether the multifunctional medication metformin could be used to reduce disease in the dy2J/dy2J mouse model of LAMA2-CMD. First, we show gender disparity for several pathological hallmarks of LAMA2-CMD. Second, we demonstrate that metformin treatment significantly increases weight gain and energy efficiency, enhances muscle function and improves skeletal muscle histology in female dy2J/dy2J mice (and to a lesser extent in dy2J/dy2J males). Thus, our current data suggest that metformin may be a potential future supportive treatment that improves many of the pathological characteristics of LAMA2-CMD.
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| 14. |
- Gawlik, Kinga, et al.
(författare)
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Deletion of integrin α7 subunit does not aggravate the phenotype of laminin α2 chain-deficient mice.
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Laminin-211 is a major constituent of the skeletal muscle basement membrane, exerting its biological functions by binding to cell surface receptors integrin α7β1 and dystroglycan (the latter is part of the dystrophin-glycoprotein complex). The importance of these molecules for normal muscle function is underscored by the fact that their respective deficiency leads to different forms of muscular dystrophy with different severity in humans and animal models. We recently demonstrated that laminin α2 chain and members of the dystrophin-glycoprotein complex have overlapping but non-redundant roles despite being part of the same adhesion complex. To analyse whether laminin-211 and integrin α7 subunit have non-redundant functions we generated mice deficient in laminin α2 chain and integrin α7 subunit (dy(3K)/itga7). We show that lack of both molecules did not exacerbate the severe phenotype of laminin α2-chain deficient animals. They displayed the same weight, survival and dystrophic pattern of muscle biopsy, with similar degree of inflammation and fibrosis. These data suggest that laminin-211 and integrin α7β1 have intersecting roles in skeletal muscle.
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| 15. |
- Gawlik, Kinga, et al.
(författare)
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Distinct roles for laminin globular domains in laminin alpha1 chain mediated rescue of murine laminin alpha2 chain deficiency.
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Laminin alpha2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Previously, we demonstrated that laminin alpha1 chain ameliorates the disease in mice. Dystroglycan and integrins are major laminin receptors. Unlike laminin alpha2 chain, alpha1 chain binds the receptors by separate domains; laminin globular (LG) domains 4 and LG1-3, respectively. Thus, the laminin alpha1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide insights into the functions of laminin alpha1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of laminin alpha1 chain that lacks the dystroglycan binding LG4-5 domains in alpha2 chain deficient mice resulted in prolonged lifespan and improved health. Importantly, diaphragm and heart muscles were corrected, whereas limb muscles were dystrophic, indicating that different muscles have different requirements for LG4-5 domains. Furthermore, the regenerative capacity of the skeletal muscle did not depend on laminin alpha1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly. CONCLUSIONS/SIGNIFICANCE: These results show that laminin alpha1LG domains and consequently their receptors have disparate functions in the neuromuscular system. Understanding these interactions could contribute to design and optimization of future medical treatment for MDC1A patients.
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| 16. |
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| 17. |
- Gawlik, Kinga I., et al.
(författare)
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Potent pro-inflammatory and profibrotic molecules, osteopontin and galectin-3, are not major disease modulators of laminin α2 chaindeficient muscular dystrophy
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- A large number of human diseases are caused by chronic tissue injury with fibrosis potentially leading to organ failure. There is a need for more effective anti-fibrotic therapies. Congenital muscular dystrophy type 1A (MDC1A) is a devastating form of muscular dystrophy caused by laminin α2 chaindeficiency. It is characterized with early inflammation and build-up of fibrotic lesions, both in patients and MDC1A mouse models (e.g. dy3K/dy3K). Despite the enormous impact of inflammation on tissue remodelling in disease, the inflammatory response in MDC1A has been poorly described. Consequently, a comprehensive understanding of secondary mechanisms (impaired regeneration, enhanced fibrosis) leading to deterioration of muscle phenotype in MDC1A is missing. We have monitored inflammatory processes in dy3K/dy3K muscle and created mice deficient in laminin α2 chain and osteopontin or galectin-3, two pro-inflammatory and pro-fibrotic molecules drastically increased in dystrophic muscle. Surprisingly, deletion of osteopontin worsened the phenotype of dy3K/dy3K mice and loss of galectin-3 did not reduce muscle pathology. Our results indicate that osteopontin could even be a beneficial immunomodulator in MDC1A. This knowledge is essential for the design of future therapeutic interventions for muscular dystrophies that aim at targeting inflammation, especially that osteopontin inhibition has been suggested for Duchenne muscular dystrophy therapy.
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| 18. |
- Gawlik, Kinga, et al.
(författare)
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Laminin {alpha}1 chain improves laminin {alpha}2 chain deficient peripheral neuropathy.
- 2006
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:18, s. 2690-2700
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Tidskriftsartikel (refereegranskat)abstract
- Absence of laminin alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A) associated with peripheral neuropathy. Hence, future therapies should be aimed at alleviating both muscle and neurological dysfunctions. Pre-clinical studies in animal models have mainly focused on ameliorating the muscle phenotype. Here we show that transgenic expression of laminin alpha1 chain in muscles and the peripheral nervous system of laminin alpha2 chain deficient mice reduced muscular dystrophy and largely corrected the peripheral nerve defects. The presence of laminin alpha1 chain in the peripheral nervous system resulted in near-normal myelination, restored Schwann cell basement membranes and improved rotarod performance. In summary, we postulate that laminin alpha1 chain is an excellent substitute for laminin alpha2 chain in multiple tissues and suggest that treatment with laminin alpha1 chain may be beneficial for MDC1A in humans.
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| 19. |
- Gawlik, Kinga, et al.
(författare)
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Laminin {alpha}1 chain reduces muscular dystrophy in laminin {alpha}2 chain deficient mice.
- 2004
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 13:16, s. 1775-1784
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Tidskriftsartikel (refereegranskat)abstract
- Laminin (LN) {alpha}2 chain deficiency in humans and mice leads to severe forms of congenital muscular dystrophy (CMD). Here, we investigated whether LN{alpha}1 chain in mice can compensate for the absence of LN{alpha}2 chain and prevent the development of muscular dystrophy. We generated mice expressing a LN{alpha}1 chain transgene in skeletal muscle of LN{alpha}2 chain deficient mice. LN{alpha}1 is not normally expressed in muscle, but the transgenically produced LN{alpha}1 chain was incorporated into muscle basement membranes, and normalized the compensatory changes of expression of certain other laminin chains ({alpha}4, ß2). In 4-month-old mice, LN{alpha}1 chain could fully prevent the development of muscular dystrophy in several muscles, and partially in others. The LN{alpha}1 chain transgene not only reversed the appearance of histopathological features of the disease to a remarkable degree, but also greatly improved health and longevity of the mice. Correction of LN{alpha}2 chain deficiency by LN{alpha}1 chain may serve as a paradigm for gene therapy of CMD in patients.
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| 20. |
- Gawlik, Kinga, et al.
(författare)
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Laminin alpha1 chain mediated reduction of laminin alpha2 chain deficient muscular dystrophy involves integrin alpha7beta1 and dystroglycan.
- 2006
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Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 580:7, s. 1759-1765
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Tidskriftsartikel (refereegranskat)abstract
- Transgenically introduced laminin (LN) α1 chain prevents muscular dystrophy in LNα2 chain deficient mice. We now report increased integrin α7Bβ1D synthesis in dystrophic LNα2 chain deficient muscle. Yet, immunofluorescence demonstrated a reduced expression of integrin α7B subunit at the sarcolemma. Transgenic expression of LNα1 chain reconstituted integrin α7B at the sarcolemma. Expression of α- and β-dystroglycan is enhanced in LNα2 chain deficient muscle and normalized by transgenic expression of LNα1 chain. We suggest that LNα1 chain in part ameliorates the development of LNα2 chain deficient muscular dystrophy by retaining the binding sites for integrin α7Bβ1D and α-dystroglycan, respectively.
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| 21. |
- Gawlik, Kinga, et al.
(författare)
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Loss of Dystrophin and β-Sarcoglycan, Respectively, Significantly Exacerbates the Phenotype of Laminin α2 Chain-Deficient Animals.
- 2014
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 184:3, s. 740-752
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Tidskriftsartikel (refereegranskat)abstract
- The adhesion molecule laminin α2 chain interacts with the dystrophin-glycoprotein complex, contributes to normal muscle function, and protects skeletal muscles from damage. Complete loss of the laminin α2 chain in mice results in a severe muscular dystrophy phenotype and death at approximately 3 weeks of age. However, it is not clear if the remaining members of the dystrophin-glycoprotein complex further protect laminin α2 chain-deficient skeletal muscle fibers from degeneration. Hence, we generated mice deficient in laminin α2 chain and dystrophin (dy(3K)/mdx) and mice devoid of laminin α2 chain and β-sarcoglycan (dy(3K)/Sgcb). Severe muscular dystrophy and a lack of nourishment inevitably led to massive muscle wasting and death in double-knockout animals. The dy(3K)/Sgcb mice were generally more severely affected than dy(3K)/mdx mice. However, both double-knockout strains displayed exacerbated muscle degeneration, inflammation, fibrosis, and reduced life span (5 to 13 days) compared with single-knockout animals. However, neither extraocular nor cardiac muscle was affected in double-knockout animals. Our results suggest that, although laminin α2 chain, dystrophin, and β-sarcoglycan are all part of the same adhesion complex, they have complementary, but nonredundant, roles in maintaining sarcolemmal integrity and protecting skeletal muscle fibers from damage. Moreover, the double-knockout mice could potentially serve as models in which to study extremely aggressive muscle-wasting conditions.
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| 22. |
- Gawlik, Kinga, et al.
(författare)
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Skeletal muscle laminin and MDC1A: pathogenesis and treatment strategies.
- 2011
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Ingår i: Skeletal Muscle. - : Springer Science and Business Media LLC. - 2044-5040. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Laminin-211 is a cell-adhesion molecule that is strongly expressed in the basement membrane of skeletal muscle. By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events. The importance of laminin-211 in skeletal muscle is evident from merosin-deficient congenital muscular dystrophy type 1A (MDC1A), in which absence of the α2 chain of laminin-211 leads to skeletal muscle dysfunction. MDC1A is the commonest form of congenital muscular dystrophy in the European population. Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death. Mice with laminin α2 chain deficiency have analogous phenotypes, and are reliable models for studies of disease mechanisms and potential therapeutic approaches. In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions. We will also discuss the molecular pathogenesis of MDC1A and advances toward the development of treatment.
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| 23. |
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| 24. |
- Gawlik, Kinga, et al.
(författare)
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Transgenic Expression of Laminin α1 Chain Does Not Prevent Muscle Disease in the mdx Mouse Model for Duchenne Muscular Dystrophy.
- 2011
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 178:4, s. 1728-1737
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Tidskriftsartikel (refereegranskat)abstract
- Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder, and one of the most frequently encountered, but one for which there is as yet no treatment. Laminin-111 protein therapy was recently shown to be a promising approach to prevent muscle disease in the mdx mouse model of DMD. The present study demonstrated that transgenic expression of laminin α1 chain in mdx animals, resulting in laminin-111 heterotrimer formation in mdx muscle, does not improve the dystrophic phenotype. The mdx mice overexpressing laminin-111 (mdxLMα1) display features of mdx littermates: dystrophic pattern of muscle biopsy, elevated creatine kinase levels, reduced muscle strength, and decreased sarcolemmal integrity. Increased expression of integrin α7 is not beneficial for mdxLMα1 muscle, and components of the dystrophin-glycoprotein complex are not restored at the sarcolemma on laminin-111 overexpression. In summary, further studies are needed to verify the functionality of laminin-111 protein therapy in DMD and to describe the molecular events resulting from this approach.
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| 25. |
- Gawlik, Kinga, et al.
(författare)
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Transgenic overexpression of laminin 1 chain in laminin 2 chain-deficient mice rescues the disease throughout the lifespan
- 2010
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Ingår i: Muscle and Nerve. - : Wiley. - 0148-639X .- 1097-4598. ; 42:1, s. 30-37
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Tidskriftsartikel (refereegranskat)abstract
- Several approaches to treat laminin alpha 2 chain-deficient congenital muscular dystrophy (MDC1A) in mouse models have been undertaken. Most have shown promising results in young animals. However, older animals have only been characterized to some extent. Herein we analyze the lifespan of laminin alpha 2 chain deficient mice with transgenic overexpression of laminin alpha 1 chain. Further outcome measures included internalized myonuclei, heart fibrosis, grip strength, and serum creatine kinase activity. We show that laminin alpha 2-chain-deficient animals that overexpress laminin alpha 1 chain survive to up to 1.5-2 years of age. Furthermore, they displayed improved skeletal and heart muscle morphology, near-normal muscle strength, and normalized creatine kinase levels. Such an improvement of the dystrophic phenotype that persists to old age has not been previously demonstrated in mice. Our findings hold promise with regard to the efficient treatment of MDC1A patients in the future. Muscle Nerve 42: 30-37, 2010
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