Wnt signaling and metaphyseal bone healing

Abstract: 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.