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Wnt gene expression during metaphyseal bone healing under different load conditions
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
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.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Bone Wnt signalling has been presented as one of the key pathways through which bone responds to mechanical load. This pathway is also active during the healing process after bone trauma. Bone healing can be improved by pharmacological modulation of Wnt signalling. We investigated how the expression of several Wntrelated genes changed due to trauma and unloading in metaphyseal bone.

20 male rats had one hind limb unloaded by intramuscular Botox injections. In half of the animals a hole was drilled bilaterally in the proximal tibia. After 7 days, a cylindrical biopsy was taken from the bone surrounding the hole and at a corresponding site in animals without trauma. The biopsies were analyzed for the mRNA expression of Wnt1, Wnt3a, Wnt4, Wnt5a, Wnt5b, Sost, Dkk1, Dkk2, Sfrp1, Sfrp4, Lrp5, Lrp6, Wisp1, Wif1 and Wnt10b.

Trauma led to upregulation of most of the studied genes. This effect was most evident in unloaded bone, where 8 genes were upregulated, among them Wnt receptors, ligands and inhibitors. Unloading increased the expression of Sost in untraumatized bone, but did not significantly influence the other genes.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71285OAI: oai:DiVA.org:liu-71285DiVA: diva2:446995
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2011-10-10Bibliographically 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.
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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Sandberg, OlofAspenberg, Per

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