title: Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy.
abstract: Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD.
  
  
  
  Thirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks.
  
  
  
  Treatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral μCT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P < 0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treated mice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P < 0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice.
  
  
  
  Our results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment of musculoskeletal disorders.
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, FI-20520, Turku, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Puolakkainen
authors.affiliation: Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland.|Institute of Dentistry, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Hongqian
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Kainulainen
authors.affiliation: Department of Physiology, University of Helsinki, Helsinki, Finland.
authors.forename: Arja
authors.initials: A
authors.lastname: Pasternack
authors.affiliation: Centre for Physical Activity and Nutrition Research, Deakin University, Melbourne, Australia.
authors.forename: Timo
authors.initials: T
authors.lastname: Rantalainen
authors.affiliation: Department of Physiology, University of Helsinki, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku, Turku, Finland.|Department of Oral Diagnostic Sciences, Institute of Dentistry, University of Eastern Finland, Kuopio, Finland.|Kuopio University Hospital, Kuopio, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Heikinheimo
authors.affiliation: Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland.|Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Juha J
authors.initials: JJ
authors.lastname: Hulmi
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, FI-20520, Turku, Finland. Riku.kiviranta@utu.fi.|Department of Endocrinology, Turku University Hospital, Turku, Finland. Riku.kiviranta@utu.fi.
authors.forename: Riku
authors.initials: R
authors.lastname: Kiviranta
mesh_terms: D030301:Activin Receptors, Type II / Q000627:therapeutic use*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D020388:Muscular Dystrophy, Duchenne; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010805:Physical Conditioning, Animal; D012995:Solubility
chemical_list: D030301:Activin Receptors, Type II; C425584:activin receptor type II-B
keywords: Animal models; Bone μCT; Bone-muscle interactions; Exercise; TGF-βs