Abstracts Biological Sciences

Determining the Role of Sost and Sostdc1 During Fracture Healing

by Cristal Yee

The bone is a dynamic organ, often changing throughout the course of the human lifespan with its continuous remodeling, laying down new bone and resorbing old bone. With age, the bone becomes increasingly porous and mechanically unstable, leading to the development of osteoporosis in some individuals. Elderly patients with osteoporosis are at an increased risk of fracturing their bones which contributes to a higher mortality rate. Recent studies have revealed that type 1 diabetic mellitus (T1DM) patients also have an osteoporotic bone phenotype and impaired fracture healing, independent of age. Currently, there is a lack of available treatments that can improve impaired healing and directly enhance bone formation. Therefore, there is a great need for developing new therapies that can not only aid type 1 diabetic patients with osteoporosis to improve bone phenotype, but that could also aid patients with difficult or impaired fracture healing. In this thesis, I will be discussing the role of Wnt signaling and Sclerostin, a Wnt antagonist that negatively regulates bone formation, in the content of fracture repair. Wnt signaling is involved during development and homeostasis in both mammals and non-mammals, revealing its conservative role throughout evolution. In Drosophila melanogaster development, Wingless (wg), an orthologue of Wnt-1, is involved in segment polarity by restricting engrailed expression and forming parasegments. In Caenorhabditis elegans, Wnt signaling is involved in gut development by inducing endoderm-mesoderm precursor cells (EMS) division to endodermal (E) cells (gut lineage founder cells) and in body axis formation in Xenopus laevis development. Wnt signaling is also involved in bone formation as observed in both loss-of-function and gain-of-function of Sost, a Wnt antagonist, which results in either increased bone formation or decreased bone formation respectfully. Sostdc1, a paralog of Sost, is also a Wnt antagonist that has been shown to regulate tooth development and most recently to be expressed in the periosteum, a source of stem cells that is active upon fracture injury, suggesting that Sostdc1 may have a potential role during fracture repair. In this dissertation, we will also be discussing how Sostdc1 is involved during bone fracture repair and potential therapy applications. Using a drug induced type 1 diabetic mouse, a model of impaired fracture healing, we will examine how Sost antibody treatment can improve both the osteoporosis phenotype as well as the impaired fracture healing in diabetic mice by enhancing bone formation. We will also briefly characterize another type 1 diabetic mouse model, the Akita mice, which carries a mutation in the insulin gene, to provide another potential diabetic mouse model to be used in fracture healing studies. Lastly, we will examine Sostdc1 role during fracture healing and reveal enhanced periosteum activity observed in Sostdc1 knockout mice.