title: Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered.
abstract: Osteocyte sclerostin is regulated by loading and disuse in mouse tibiae but is more closely related to subsequent local osteogenesis than the peak strains engendered.
  
  
  BACKGROUND
  The purpose of this study was to assess the relationship between loading-related change in osteocyte sclerostin expression, local strain magnitude, and local bone modeling/remodeling.
  
  
  METHODS
  The right tibiae of 19-week-old female C57BL/6 mice were subjected to non-invasive, dynamic axial loading and/or to sciatic neurectomy-induced disuse. The sclerostin status of osteocytes was evaluated immunohistochemically, changes in bone mass by micro-computed tomography, new bone formation by histomorphometry, and loading-induced strain by strain gauges and finite element analysis.
  
  
  RESULTS
  In cortical bone of the tibial shaft, loading engendered strains of similar peak magnitude proximally and distally. Proximally, sclerostin-positive osteocytes decreased and new bone formation increased. Distally, there was neither decrease in sclerostin-positive osteocytes nor increased osteogenesis. In trabecular bone of the proximal secondary spongiosa, loading decreased sclerostin-positive osteocytes and increased bone volume. Neither occurred in the primary spongiosa. Disuse increased sclerostin-positive osteocytes and decreased bone volume at all four sites. Loading reversed this sclerostin upregulation to a level below baseline in the proximal cortex and secondary spongiosa.
  
  
  CONCLUSIONS
  Loading-related sclerostin downregulation in osteocytes of the mouse tibia is associated preferentially with regions where new bone formation is stimulated rather than where high peak strains are engendered. The mechanisms involved remain unclear, but could relate to peak surface strains not accurately reflecting the strain-related osteogenic stimulus or that sclerostin regulation occurs after sufficient signal processing to distinguish between local osteogenic and non-osteogenic responses.
authors.affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Moustafa
authors.forename: T
authors.initials: T
authors.lastname: Sugiyama
authors.forename: J
authors.initials: J
authors.lastname: Prasad
authors.forename: G
authors.initials: G
authors.lastname: Zaman
authors.forename: T S
authors.initials: TS
authors.lastname: Gross
authors.forename: L E
authors.initials: LE
authors.lastname: Lanyon
authors.forename: J S
authors.initials: JS
authors.lastname: Price
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D007103:Immobilization / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D010011:Osteocytes / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D012584:Sciatic Nerve / Q000601:surgery; D013314:Stress, Mechanical; D013977:Tibia / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D016474:Weight-Bearing / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse