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Assessment of the effect of systemic delivery of sclerostin antibodies on Wnt signaling in distraction osteogenesis

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Abstract

Sclerostin is a known inhibitor of the Wnt signaling pathway which is involved in osteogenesis and, when inactivated, stimulates bone formation. To our knowledge, this effect has not been studied in the context of distraction osteogenesis (DO). Tibial DO was conducted on a total of 24 wild-type mice, which were then divided into 2 groups—a saline injection group (control) and an anti-sclerostin (Scl-Ab) injection group (treatment). The mice in the treatment group received 100 mg/kg intravenous injections of the antibody weekly until killing. The 12 mice in each group were subdivided into four time points according to post-osteotomy time of killing—11 days (mid-distraction), 17 days (late distraction), 34 days (mid-consolidation) and 51 days (late consolidation), with 3 mice per subgroup. After killing, the tibia specimens were collected for immunohistochemical analysis. Our results show 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, downregulation of the inhibitors of this pathway was noted in the treatment group when compared with the placebo group. Furthermore, LRP-5 showed a significant increase in expression in the treatment group. 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.

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Acknowledgements

We thank Novartis Institutes of Biomedical Research (NIBR) for the provision of the sclerostin antibody, which was generated in collaboration with MorphoSys AG. We are grateful to Guylaine Bedard for preparation of the figures. This study was supported by the Shriners of North America, The Canadian Institute for Health Research (Canada), University of Dammam (Dammam, Saudi Arabia) and King Abdulaziz University (Jeddah, Saudi Arabia).

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Authors and Affiliations

  1. Division of Orthopaedic Surgery, Shriners Hospital for Children, Montreal Children Hospital, McGill University, 1003 Decarie Blvd, Montreal, QC, H4A 0A9, Canada

    Mohammad M. Alzahrani, Asim M. Makhdom, Frank Rauch, Dominique Lauzier, Maria Kotsiopriftis, Saber Ghadakzadeh & Reggie C. Hamdy

  2. Department of Orthopaedic Surgery, University of Dammam, Dammam, Saudi Arabia

    Mohammad M. Alzahrani

  3. Department of Orthopaedic Surgery, King Abdulaziz University, Jeddah, Saudi Arabia

    Asim M. Makhdom

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  1. Mohammad M. Alzahrani
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Contributions

MM: Data collection, interpretation and manuscript preparation. AMM: Performed surgeries, data collection, interpretation and manuscript preparation. FR: Manuscript preparation and revision. DL: Immunohistochemical aspect and manuscript revision. MK: Immunohistochemical aspect and manuscript revision. SG: Manuscript preparation and final revision. RCH: Manuscript preparation and final revision.

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Correspondence to Mohammad M. Alzahrani.

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Alzahrani, M.M., Makhdom, A.M., Rauch, F. et al. Assessment of the effect of systemic delivery of sclerostin antibodies on Wnt signaling in distraction osteogenesis. J Bone Miner Metab 36, 373–382 (2018). https://doi.org/10.1007/s00774-017-0847-2

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