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The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions
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.
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, USA.
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
2011 (English)In: BONE, ISSN 8756-3282, Vol. 48, no 5, 988-996 p.Article in journal (Refereed) Published
Abstract [en]

The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, mu CT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam. , 2011. Vol. 48, no 5, 988-996 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68352DOI: 10.1016/j.bone.2011.02.008ISI: 000289879900005OAI: oai:DiVA.org:liu-68352DiVA: diva2:418134
Note
Original Publication: Fredrik Agholme, Hanna Isaksson, Stuart Kuhstoss and Per Aspenberg, The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions, 2011, BONE, (48), 5, 988-996. http://dx.doi.org/10.1016/j.bone.2011.02.008 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Available from: 2011-05-20 Created: 2011-05-20 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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1253
National Category
Medical and Health Sciences
Identifiers
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)
Opponent
Supervisors
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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