title: The central nervous system (CNS)-independent anti-bone-resorptive activity of muscle contraction and the underlying molecular and cellular signatures.
abstract: BACKGROUND
  Mechanisms by which muscle regulates bone are poorly understood.
  
  
  RESULTS
  Electrically stimulated muscle contraction reversed elevations in bone resorption and increased Wnt signaling in bone-derived cells after spinal cord transection.
  
  
  CONCLUSIONS
  Muscle contraction reduced resorption of unloaded bone independently of the CNS, through mechanical effects and, potentially, nonmechanical signals (e.g. myokines).
  
  
  CONCLUSIONS
  The study provides new insights regarding muscle-bone interactions. Muscle and bone work as a functional unit. Cellular and molecular mechanisms underlying effects of muscle activity on bone mass are largely unknown. Spinal cord injury (SCI) causes muscle paralysis and extensive sublesional bone loss and disrupts neural connections between the central nervous system (CNS) and bone. Muscle contraction elicited by electrical stimulation (ES) of nerves partially protects against SCI-related bone loss. Thus, application of ES after SCI provides an opportunity to study the effects of muscle activity on bone and roles of the CNS in this interaction, as well as the underlying mechanisms. Using a rat model of SCI, the effects on bone of ES-induced muscle contraction were characterized. The SCI-mediated increase in serum C-terminal telopeptide of type I collagen (CTX) was completely reversed by ES. In ex vivo bone marrow cell cultures, SCI increased the number of osteoclasts and their expression of mRNA for several osteoclast differentiation markers, whereas ES significantly reduced these changes; SCI decreased osteoblast numbers, but increased expression in these cells of receptor activator of NF-κB ligand (RANKL) mRNA, whereas ES increased expression of osteoprotegerin (OPG) and the OPG/RANKL ratio. A microarray analysis revealed that ES partially reversed SCI-induced alterations in expression of genes involved in signaling through Wnt, FSH, parathyroid hormone (PTH), oxytocin, and calcineurin/nuclear factor of activated T-cells (NFAT) pathways. ES mitigated SCI-mediated increases in mRNA levels for the Wnt inhibitors DKK1, sFRP2, and sclerostin in ex vivo cultured osteoblasts. Our results demonstrate an anti-bone-resorptive activity of muscle contraction by ES that develops rapidly and is independent of the CNS. The pathways involved, particularly Wnt signaling, suggest future strategies to minimize bone loss after immobilization.
authors.affiliation: Departments of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. weiping.qin@mssm.edu
authors.forename: Weiping
authors.initials: W
authors.lastname: Qin
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Jay
authors.initials: J
authors.lastname: Cao
authors.forename: Yuanzhen
authors.initials: Y
authors.lastname: Peng
authors.forename: Lauren
authors.initials: L
authors.lastname: Collier
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.forename: Graham
authors.initials: G
authors.lastname: Creasey
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Qin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jarvis
authors.forename: William A
authors.initials: WA
authors.lastname: Bauman
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.forename: Christopher
authors.initials: C
authors.lastname: Cardozo
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D001862:Bone Resorption / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000503:physiopathology; D024042:Collagen Type I / Q000097:blood; D004558:Electric Stimulation; D005260:Female; D005269:Femur / Q000378:metabolism / Q000473:pathology; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D024042:Collagen Type I; D015675:Osteocalcin
keywords: Bone; CNS; Gene Expression; Microarray; Muscle and Bone Interaction; Osteoblasts; Osteoclast; Osteoporosis; Spinal Cord Injury; Wnt Pathway