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Assessment of the Effect of Systemic Delivery of Sclerostin Antibodies on WNT Signaling in Distraction Osteogenesis Using Immunohistochemistry

Alzahrani, Mohammad M. and Makhdom , Asim M. and Rauch, Frank and Lauzier, Dominique and Kotsiopriftis, Maria and Hamdy, Reggie C. (2015) Assessment of the Effect of Systemic Delivery of Sclerostin Antibodies on WNT Signaling in Distraction Osteogenesis Using Immunohistochemistry. Journal of orthopaedic research.

Abstract

Introduction
Sclerostin is a known inhibitor of the WNT signaling pathway involved in osteogenesis, therefore when inactivated bone formation is stimulated. One of the potential ways of inactivation of this molecule is the sclerostin antibody injection. This antibody has been shown to improve fracture healing in the mouse model but to our knowledge its effect has not been studied in the context of distraction osteogenesis (DO).
Objective
The objective of this study was to determine the immunohistochemical effect of sclerostin antibody injection at various time points during bone formation in a wild-type mouse model of DO.
Materials and Methods
Tibial DO was conducted on a total of 24 wild type mice, which were then divided into 2 groups; saline injection group (control) and anti-sclerostin (Scl-Ab) injection group (treatment). The mice in the treatment group received 100mg/kg intravenous injections of the antibody weekly till sacrifice. The 12 mice in each group were subdivided into four time points according to time post-osteotomy for sacrifice, these were 11 days (mid-distraction), 17 days (late distraction), 34 days (mid-consolidation) and 51 days (late consolidation) with 3 mice per subgroup. The tibia specimens post-sacrifice were then collected for immunohistochemical analysis.
Results
Our results showed that the group injected with anti-sclerostin had an earlier peak (day 11) in the distraction phase of the osteogenic molecules involved in the WNT signaling pathway in comparison to the placebo group. In addition to the noted downregulation of the inhibitors of this pathway in the treatment group when compared with the placebo group. Also LRP-5 should a significant increase in expression in the treatment group.
Conclusion
Sclerostin inhibition has a significant effect on the DO process through its effect on the WNT pathway. This effect was evident through the decreased effect of sclerostin on LRP-5 and earlier upregulation of the osteogenic molecules involved in this pathway.
Clinical Relevance
This is the first report of the immunohistochemical effect of sclerostin antibody injection in DO, which could be a potential treatment modality to accelerate healing of the gap created during the process of DO, thus reducing the complications associated with this.

Item Type: Article
Keywords: WNT signaling, immunostaning, distraction osteogenesis, sclerostin antibody, immunohistochemistry, TGF-beta/Smad signaling
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22916

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