title: Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression.
abstract: BACKGROUND
  No treatment to date is available which specifically targets bone formation in ankylosing spondylitis (AS). Several recent studies have shown that sclerostin (SOST), a Wnt inhibitor specific to osteocytes and chondrocytes, is down-regulated in AS patients. This suggests Wnt signalling may be upregulated, and application of exogenous recombinant SOST (rSOST) may inhibit Wnt signalling and slow pathological bone formation.
  
  
  METHODS
  The proteoglycan-induced spondylitis (PGISp) mouse model in which we have previously demonstrated downregulated SOST expression, was used for this study. Mice were injected with 2.5 ug rSOST/day for a period of 8 weeks following induction of disease. Axial skeleton disease development was assessed by histology and skeletal changes examined using DEXA.
  
  
  RESULTS
  rSOST treatment had no effect on peripheral or axial disease development, bone density or disease severity. Injected rSOST was stable over 8 h and residual levels were evident 24 h after injection, resulting in a cumulative increase in SOST serum levels over the treatment time course. Immunohistochemical examination of SOST levels within the joints in non-rSOST treated PGISp mice showed a significant decrease in the percentage of positive osteocytes in the unaffected joints compared to the affected joints, while no difference was seen in rSOST treated mice. This suggests that rSOST treatment increases the number of SOST-positive osteocytes in unaffected joints but not affected joints, despite having no impact on the number of joints affected by disease.
  
  
  CONCLUSIONS
  Although not disease-modifying, rSOST treatment did appear to regulate SOST levels in the joints suggesting biological activity. Further dose response studies are required and SOST may require modifications to improve its bone targeting ability in order to affect tissue formation to a meaningful level in this model.
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. k.haynes1@uq.edu.au.
authors.forename: Katelin R
authors.initials: KR
authors.lastname: Haynes
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. hsu-wen.tseng@mater.uq.edu.au.
authors.forename: Hsu-Wen
authors.initials: HW
authors.lastname: Tseng
authors.affiliation: Musculoskeletal Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland. michaela.kneissel@novartis.com.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
authors.affiliation: Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, USA. Tibor_Glant@rush.edu.
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. matt.brown@uq.edu.au.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. gethin.thomas@uq.edu.au.
authors.forename: Gethin P
authors.initials: GP
authors.lastname: Thomas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005819:Genetic Markers; D057809:HEK293 Cells; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013167:Spondylitis, Ankylosing / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human