title: Potent pro-inflammatory and pro-fibrotic molecules, osteopontin and galectin-3, are not major disease modulators of laminin α2 chain-deficient muscular dystrophy.
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 chain-deficiency. 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/dy3Kmuscle 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/dy3Kmice 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.
authors.affiliation: Department of Experimental Medical Science, Muscle Biology Unit, Lund University, Sweden.
authors.forename: Kinga I
authors.initials: KI
authors.lastname: Gawlik
authors.affiliation: Department of Experimental Medical Science, Muscle Biology Unit, Lund University, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Holmberg
authors.affiliation: Department of Experimental Medical Science, Experimental Neuroinflammation Laboratory, Lund University, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Svensson
authors.affiliation: Department of Experimental Medical Science, Muscle Biology Unit, Lund University, Sweden.
authors.forename: Mikaela
authors.initials: M
authors.lastname: Einerborg
authors.affiliation: Department of Experimental Medical Science, Muscle Biology Unit, Lund University, Sweden.
authors.forename: Bernardo M S
authors.initials: BM
authors.lastname: Oliveira
authors.affiliation: Department of Experimental Medical Science, Experimental Neuroinflammation Laboratory, Lund University, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Deierborg
authors.affiliation: Department of Experimental Medical Science, Muscle Biology Unit, Lund University, Sweden.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Durbeej
mesh_terms: D000818:Animals; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007797:Laminin / Q000235:genetics*; D008297:Male; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000150:complications / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype
chemical_list: D037502:Galectin 3; D018836:Inflammation Mediators; D007797:Laminin; C485095:Lgals3 protein, mouse; C506896:Spp1 protein, mouse; C102645:laminin alpha 2; D053495:Osteopontin