title: Impaired bone homeostasis in amyotrophic lateral sclerosis mice with muscle atrophy.
abstract: There is an intimate relationship between muscle and bone throughout life. However, how alterations in muscle functions in disease impact bone homeostasis is poorly understood. Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive muscle atrophy. In this study we analyzed the effects of ALS on bone using the well established G93A transgenic mouse model, which harbors an ALS-causing mutation in the gene encoding superoxide dismutase 1. We found that 4-month-old G93A mice with severe muscle atrophy had dramatically reduced trabecular and cortical bone mass compared with their sex-matched wild type (WT) control littermates. Mechanically, we found that multiple osteoblast properties, such as the formation of osteoprogenitors, activation of Akt and Erk1/2 pathways, and osteoblast differentiation capacity, were severely impaired in primary cultures and bones from G93A relative to WT mice; this could contribute to reduced bone formation in the mutant mice. Conversely, osteoclast formation and bone resorption were strikingly enhanced in primary bone marrow cultures and bones of G93A mice compared with WT mice. Furthermore, sclerostin and RANKL expression in osteocytes embedded in the bone matrix were greatly up-regulated, and β-catenin was down-regulated in osteoblasts from G93A mice when compared with those of WT mice. Interestingly, calvarial bone that does not load and long bones from 2-month-old G93A mice without muscle atrophy displayed no detectable changes in parameters for osteoblast and osteoclast functions. Thus, for the first time to our knowledge, we have demonstrated that ALS causes abnormal bone remodeling and defined the underlying molecular and cellular mechanisms.
authors: From the Department of Biochemistry and.
authors: Ke
authors: K
authors: Zhu
authors: Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612.
authors: Jianxun
authors: J
authors: Yi
authors: Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612.
authors: Yajuan
authors: Y
authors: Xiao
authors: From the Department of Biochemistry and.
authors: Yumei
authors: Y
authors: Lai
authors: From the Department of Biochemistry and.
authors: Pingping
authors: P
authors: Song
authors: From the Department of Biochemistry and.
authors: Wei
authors: W
authors: Zheng
authors: From the Department of Biochemistry and.
authors: Hongli
authors: H
authors: Jiao
authors: Department of Surgery and.
authors: Jie
authors: J
authors: Fan
authors: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and.
authors: Chuanyue
authors: C
authors: Wu
authors: From the Department of Biochemistry and.
authors: Di
authors: D
authors: Chen
authors: Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612.
authors: Jingsong
authors: J
authors: Zhou
authors: From the Department of Biochemistry and Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China Guozhi_Xiao@rush.edu xiao.gz@sustc.edu.cn.
authors: Guozhi
authors: G
authors: Xiao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015519:Bone Density; D001854:Bone Marrow Cells / Q000502:physiology; D016723:Bone Remodeling; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D053245:RANK Ligand / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; C000606290:SOD1 protein, human; C486030:Sost protein, mouse; C505689:Tnfsf11 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig Disease); Bone; Muscle Atrophy; Osteoblast; Osteoclast
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