title: Glycoprotein nonmetastatic melanoma protein B ameliorates skeletal muscle lesions in a SOD1G93A mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons and subsequent muscular atrophy. The quality of life of patients with ALS is significantly improved by ameliorating muscular symptoms. We previously reported that glycoprotein nonmetastatic melanoma protein B (GPNMB; osteoactivin) might serve as a target for ALS therapy. In the present study, superoxide dismutase 1/glycine residue 93 changed to alanine (SOD1(G93A) ) transgenic mice were used as a model of ALS. Expression of the C-terminal fragment of GPNMB was increased in the skeletal muscles of SOD1(G93A) mice and patients with sporadic ALS. SOD1(G93A) /GPNMB transgenic mice were generated to determine whether GPNMB expression ameliorates muscular symptoms. The weight and cross-sectional area of the gastrocnemius muscle, number and cross-sectional area of myofibers, and denervation of neuromuscular junctions were ameliorated in SOD1(G93A) /GPNMB vs. SOD1(G93A) mice. Furthermore, direct injection of a GPNMB expression plasmid into the gastrocnemius muscle of SOD1(G93A) mice increased the numbers of myofibers and prevented myofiber atrophy. These findings suggest that GPNMB directly affects skeletal muscle and prevents muscular pathology in SOD1(G93A) mice and may therefore serve as a target for therapy of ALS.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nagahara
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Noda
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohuchi
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology* / Q000628:therapy*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000276:immunology; D016708:Synaptophysin / Q000378:metabolism
chemical_list: C503042:GPNMB protein, human; D008562:Membrane Glycoproteins; D016708:Synaptophysin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: ALS; GPNMB; amyotrophic lateral sclerosis; glycoprotein nonmetastatic melanoma protein B; neuromuscular junction; skeletal muscle; sporadic ALS; transgenic mouse