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Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
Amgen Inc.
University of Eastern Finland.
Amgen Inc.
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2010 (English)In: JOURNAL OF BONE AND MINERAL RESEARCH, ISSN 0884-0431, Vol. 25, no 11, 2412-2418 p.Article in journal (Refereed) Published
Abstract [en]

Sclerostin is the product of the SOST gene Loss of-function mutations in the SOST gene result in a high bone-mass phenotype demonstrating that sclerostin is a negative regulator of bone mass Primarily expressed by osteocytes in bone sclerostin is reported to bind the LRP5/6 receptor thereby antagonizing canonical Wnt signaling and negatively regulating bone formation We therefore investigated whether systemic administration of a sclerostin neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks In four groups, the screws were tested for pull out strength At the time of euthanasia a similar screw also was inserted in the contralateral tibia and pull-out tested immediately Sclerostin antibody significantly increased the pull out force by almost 50% compared with controls after 2 and 4 weeks Also the screws inserted at the time of euthanasia showed increased pull out force Micro-computed tomography (mu CT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw There also was a general increase in trabecular thickness in cancellous bone Thus as measured by the amount of bone and its mechanical resistance the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone

Place, publisher, year, edition, pages
American Society for Bone and Mineral Research , 2010. Vol. 25, no 11, 2412-2418 p.
Keyword [en]
bone formation;implants;bone repair;sclerostin;antibody
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-62733DOI: 10.1002/jbmr.135ISI: 000284133500016PubMedID: 20499342OAI: diva2:374233
Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2011-10-10
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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