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Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
Department of Applied physics, University of Eastern Finland, Kuopio, Finland.
Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
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2011 (English)In: Acta Orthopaedica, ISSN 1745-3674, Vol. 82, no 5, 628-632 p.Article in journal (Refereed) Published
Abstract [en]

Background and purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.

Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.

Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.

Interpretation: Scl-Ab increases bone formation and screwfixation to a similar degree in loaded and unloaded bone.

Place, publisher, year, edition, pages
Taylor and Francis , 2011. Vol. 82, no 5, 628-632 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-71284DOI: 10.3109/17453674.2011.625539OAI: diva2:446989
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2014-10-17Bibliographically approved
In thesis
1. Wnt signaling and metaphyseal bone healing
Open this publication in new window or tab >>Wnt signaling and metaphyseal bone healing
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis relates to some new aspects on the regulation of bone healing. In the last few years, Wnt-signaling has been shown to play a central role in bone biology. As well as being involved in bone maintenance and repair, Wnt-signaling has been presented as one of the key pathways through which bone responds to mechanical load. Two secreted extracellular inhibitors of Wnt-signaling, sclerostin and dickkopf-1 are potent negative regulators of bone formation.

Using a rat fracture model we investigated how metaphyseal bone healing is influenced by changes in Wnt-signaling.

Antibodies were used to suppress levels of sclerostin and dickkopf-1, and thereby increase Wnt-signaling. Primarily, we investigated if those antibody treatments lead to improved bone healing. Also, we investigated if the response was coupled to the loading conditions of the bone.

Our findings suggest that suppression of either sclerostin or dickkopf-1 leads to increased bone formation and improved bone healing. Apart from just having an effect on healing, the treatment also improved bone formation in other parts of the skeleton. Depending on the loading conditions, the effects were different. Dickkopf-1 appeared to have a stronger effect on bone volume density in unloaded bone, implying a role mainly in mechano-transduction, while sclerostin had similar effect in both loaded and unloaded bone. To confirm these findings, we studied how the expression of several Wnt-related genes changed due to trauma and unloading in metaphyseal bone. We found that trauma led to upregulation of most of the genes with the largest effect seen in the unloaded bone. In untraumatized bone, there was mainly an effect on the sclerostin gene.

In conclusion, antibodies against sclerostin and dickkopf-1 appear to be able to improve metaphyseal bone healing. There appear to be some differences in how the effect of the two antibodies manifests itself, especially if the loading conditions of the bone are altered. These findings suggest a potential for clinical use to shorten fracture healing time.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 34 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1253
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-71287 (URN)978-91-7393-103-8 (ISBN)
Public defence
2011-10-14, Nils-Holger salen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2011-10-12Bibliographically approved

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Agholme, FredrikAspenberg, Per
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Orthopaedics and Sports MedicineFaculty of Health SciencesDepartment of Orthopaedics in Linköping
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