title: Transient muscle paralysis degrades bone via rapid osteoclastogenesis.
abstract: A unilateral injection of botulinum toxin A (BTxA) in the calf induces paralysis and profound loss of ipsalateral trabecular bone within days. However, the cellular mechanism underlying acute muscle paralysis-induced bone loss (MPIBL) is poorly understood. We hypothesized that MPIBL arises via rapid and extensive osteoclastogenesis. We performed a series of in vivo experiments to explore this thesis. First, we observed elevated levels of the proosteoclastogenic cytokine receptor activator for nuclear factor-κB ligand (RANKL) within the proximal tibia metaphysis at 7 d after muscle paralysis (+113%, P<0.02). Accordingly, osteoclast numbers were increased 122% compared with the contralateral limb at 5 d after paralysis (P=0.04) and MPIBL was completely blocked by treatment with human recombinant osteoprotegerin (hrOPG). Further, conditional deletion of nuclear factor of activated T-cells c1 (NFATc1), the master regulator of osteoclastogenesis, completely inhibited trabecular bone loss (-2.2±11.9%, P<0.01). All experiments included negative control assessments of contralateral limbs and/or within-animal pre- and postintervention imaging. In summary, transient muscle paralysis induced acute RANKL-mediated osteoclastogenesis resulting in profound local bone resorption. Elucidation of the pathways that initiate osteoclastogenesis after paralysis may identify novel targets to inhibit bone loss and prevent fractures.
authors: Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Antonios O
authors: AO
authors: Aliprantis
authors: Marina
authors: M
authors: Stolina
authors: Paul J
authors: PJ
authors: Kostenuik
authors: Sandra L
authors: SL
authors: Poliachik
authors: Sarah E
authors: SE
authors: Warner
authors: Steven D
authors: SD
authors: Bain
authors: Ted S
authors: TS
authors: Gross
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism / Q000517:prevention & control; D001842:Bone and Bones / Q000378:metabolism*; D019274:Botulinum Toxins, Type A / Q000633:toxicity; D002452:Cell Count; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010243:Paralysis / Q000139:chemically induced / Q000378:metabolism*; D052097:Quadriceps Muscle / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013977:Tibia / Q000378:metabolism; D013997:Time Factors
chemical_list: D050778:NFATC Transcription Factors; D053244:Osteoprotegerin; D053245:RANK Ligand; D011994:Recombinant Proteins; D019274:Botulinum Toxins, Type A