title: Sclerostin does not play a major role in the pathogenesis of skeletal complications in type 2 diabetes mellitus.
abstract: In contrast to previously reported elevations in serum sclerostin levels in diabetic patients, the present study shows that the impaired bone microarchitecture and cellular turnover associated with type 2 diabetes mellitus (T2DM)-like conditions in ZDF rats are not correlated with changes in serum and bone sclerostin expression.
  
  
  
  T2DM is associated with impaired skeletal structure and a higher prevalence of bone fractures. Sclerostin, a negative regulator of bone formation, is elevated in serum of diabetic patients. We aimed to relate changes in bone architecture and cellular activities to sclerostin production in the Zucker diabetic fatty (ZDF) rat.
  
  
  
  Bone density and architecture were measured by micro-CT and bone remodelling by histomorphometry in tibiae and femurs of 14-week-old male ZDF rats and lean Zucker controls (n = 6/group).
  
  
  
  ZDF rats showed lower trabecular bone mineral density and bone mass compared to controls, due to decreases in bone volume and thickness, along with impaired bone connectivity and cortical bone geometry. Bone remodelling was impaired in diabetic rats, demonstrated by decreased bone formation rate and increased percentage of tartrate-resistant acid phosphatase-positive osteoclastic surfaces. Serum sclerostin levels (ELISA) were higher in ZDF compared to lean rats at 9 weeks (+40 %, p < 0.01), but this difference disappeared as their glucose control deteriorated and by week 14, ZDF rats had lower sclerostin levels than control rats (-44 %, p < 0.0001). Bone sclerostin mRNA (qPCR) and protein (immunohistochemistry) were similar in ZDF, and lean rats at 14 weeks and genotype did not affect the number of empty osteocytic lacunae in cortical and trabecular bone.
  
  
  
  T2DM results in impaired skeletal architecture through altered remodelling pathways, but despite altered serum levels, it does not appear that sclerostin contributes to the deleterious effect of T2DM in rat bone.
authors.affiliation: Department of Comparative Biomedical sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK. mpereira@rvc.ac.uk.
authors.forename: M
authors.initials: M
authors.lastname: Pereira
authors.affiliation: Department of Comparative Biomedical sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: S
authors.initials: S
authors.lastname: Gohin
authors.affiliation: Department of Comparative Biomedical sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: N
authors.initials: N
authors.lastname: Lund
authors.affiliation: Department of Comparative Biomedical sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hvid
authors.affiliation: University College London, London, UK.|The University of Adelaide, Adelaide, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Smitham
authors.affiliation: University College Hospital, London, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Oddy
authors.affiliation: Kings College London, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Reichert
authors.affiliation: INSERM UMR1033 and Université de Lyon, Lyon, France.
authors.forename: D
authors.initials: D
authors.lastname: Farlay
authors.affiliation: INSERM UMR1033 and Université de Lyon, Lyon, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Roux
authors.affiliation: Department of Comparative Biomedical sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Cleasby
authors.affiliation: Department of Comparative Biomedical sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: C
authors.initials: C
authors.lastname: Chenu
mesh_terms: D017667:Adipocytes / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D015519:Bone Density / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D016723:Bone Remodeling / Q000502:physiology*; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000503:physiopathology; D002478:Cells, Cultured; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D005819:Genetic Markers / Q000235:genetics / Q000502:physiology*; D006244:Hardness; D008297:Male; D010011:Osteocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011924:Rats, Zucker; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D001786:Blood Glucose; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D012333:RNA, Messenger; C486031:Sost protein, rat
keywords: Bone; Sclerostin; Type 2 diabetes; Zucker rats