Impaired bone homeostasis in amyotrophic lateral sclerosis mice with muscle atrophy.
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.
['Zhu|Ke|K|', 'Yi|Jianxun|J|', 'Xiao|Yajuan|Y|', 'Lai|Yumei|Y|', 'Song|Pingping|P|', 'Zheng|Wei|W|', 'Jiao|Hongli|H|', 'Fan|Jie|J|', 'Wu|Chuanyue|C|', 'Chen|Di|D|', 'Zhou|Jingsong|J|', 'Xiao|Guozhi|G|']
D048868:Adaptor Proteins, Signal Transducing D000690:Amyotrophic Lateral Sclerosis D000818:Animals D015519:Bone Density D001854:Bone Marrow Cells D016723:Bone Remodeling D001842:Bone and Bones D002454:Cell Differentiation D049109:Cell Proliferation D002478:Cells, Cultured D005260:Female D006023:Glycoproteins D006801:Humans D036341:Intercellular Signaling Peptides and Proteins D008297:Male D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D018482:Muscle, Skeletal D009133:Muscular Atrophy D020125:Mutation, Missense D010006:Osteoblasts D010010:Osteoclasts D053245:RANK Ligand D013482:Superoxide Dismutase D000072105:Superoxide Dismutase-1
Bone Muscle Atrophy Osteoblast Osteoclast Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig Disease)