Osteogenesis Imperfecta (OI) is a genetic disorder characterized by low bone mass that predisposes children and adults to skeletal fracture. Most patients with OI have a mutation in one of the two genes that encode type 1 collagen. Current medical therapies for patients with OI are limited, acting by preventing bone turnover to increase bone mass and do not decrease fracture rate in all patients. Our previous work has shown that enhancing bone anabolism via the low density lipoprotein receptor related-protein 5 (LRP5) signaling pathway, either through a genetic mutation that increases signaling or administration of an antibody that binds an inhibitor of the pathway, leads to significant increases in bone mass and bone strength in several mouse models of OI caused by dominant type 1 collagen mutations. In addition, we have shown that osteoblasts from mice with OI have ER swelling that improves with increased LRP5 signaling, suggesting that protein trafficking is improved. This is important as therapies (Sclerostin antibody) are available that increase LRP5 signaling and our data suggest they will be have dual beneficial effects in patients with OI, both increasing bone matrix production and improving osteoblast function. In the present application, we propose to utilize two different mouse models of dominant OI 1) To identify the molecular mechanisms by which an Lrp5 HBM mutation improves protein trafficking of type I collagen in dominant forms of OI, 2) To determine the effect of treatment with Sclerostin antibody on osteoblast development and function in OI and 3) To determine if increased LRP5 signaling is required during osteoblast development to improve osteoblast function in dominant forms of OI. The successful completion of these aims will allow for greater understanding of the mechanisms by which increased LRP5 signaling both increases collagen production and improves osteoblast function. Together the results will show that therapies targeting LRP5 signaling, unlike other currently available treatments, not only increase collagen production but also treat the specific osteoblast dysfunction seen in OI, which may lead to better outcomes for patients.
Osteogenesis Imperfecta (OI) is a genetic disorder characterized by decreased bone strength resulting in fractures for which treatments are limited. Increasing low density lipoprotein related protein 5 (LRP5) signaling improves bone density and strength in several different mouse models of OI. This proposal aims to define the mechanisms by which LRP5 signaling improves the function of osteoblasts in OI and to determine the optimum timing of therapies targeting the LRP5 pathway to produce the maximum clinical benefit for patients.
