Wnt signaling for improved fracture healing Bone fractures are the most frequent problems observed by orthopedic surgeons all over the world. Fractures are mostly caused by trauma (fall, sports injury, road accidents) in healthy youth. However, age progression or certain diseases e.g. diabetes, cancer, osteoporosis etc, lead to higher frequency of bone fractures which are greatly impaired and result in multiple complications. Several clinical studies as well as transgenic mouse models have shown that induced Wnt signaling pathway can support accelerated bone formation. Ablation of a Wnt antagonist, sFRP1 leads to a high bone mass phenotype in later stages of life. We have shown that young mice without sFRP1 also have increased osteoblast differentiation/bone parameters and hypertrophic cartilage without adverse effects. We postulate that this balanced phenotype in the sFRP1-/- mice is a result of contribution of both canonical as well non-canonical Wnt pathways. Our objective is to examine the role of activated Wnt signaling during fracture healing, and to achieve improved fracture repair. We predict a tight regulation of Wnt signaling and a fine balance between activation of canonical and non-canonical pathways during fracture healing process. Few small molecule compounds have been reported to stimulate both canonical as well as non-canonical Wnt signaling pathways. Using these synthetic compounds to induce Wnt signaling and mimic the phenotype of sFRP1-/- mouse, we expect to translate our findings into therapies to treat fracture patients.
The proposed studies will define the contribution of Wnt signaling pathways for fracture healing, and the molecular mechanisms for accelerated fracture healing in response to induced Wnt signaling. Also, potential therapeutic agents will be examined to provide a balanced activation of Wnt signaling pathways for improved fracture healing.
|Gaur, Tripti; Hussain, Sadiq; Mudhasani, Rajini et al. (2010) Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse. Dev Biol 340:10-21|