Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression

Haynes, Katelin R., Tseng, Hsu-Wen, Kneissel, Michaela, Glant, Tibor T., Brown, Matthew A. and Thomas, Gethin P. (2015) Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression. BMC Musculoskeletal Disorders, 16 1: . doi:10.1186/s12891-015-0823-8


Author Haynes, Katelin R.
Tseng, Hsu-Wen
Kneissel, Michaela
Glant, Tibor T.
Brown, Matthew A.
Thomas, Gethin P.
Title Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression
Journal name BMC Musculoskeletal Disorders   Check publisher's open access policy
ISSN 1471-2474
Publication date 2015-11-26
Year available 2015
Sub-type Article (original research)
DOI 10.1186/s12891-015-0823-8
Open Access Status DOI
Volume 16
Issue 1
Total pages 8
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Subject 2745 Rheumatology
2732 Orthopedics and Sports Medicine
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 2.5ug 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.
Formatted 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 2.5ug 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.
Keyword Ankylosing spondylitis
Sclerostin
Wnt inhibitor
Mouse model
Bone formation
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1006450
APP1024879
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
UQ Diamantina Institute Publications
 
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