It is well established that patients with the collagen-based disease osteogenesis imperfecta (OI) have increased bone turnover (increased degradation and reduced formation). Accordingly, the reports of successful therapy in children with OI with the anti-resorptive agents bisphosphonates are quite exciting, but not unexpected. Despite this apparent success, there are still concerns surrounding the use of anti-resorptive agents in children and in women of childbearing age. Namely, the persistence of the drug in bone tissue over time could have unforeseen consequences, such as adverse effects on fetal development. In addition, it is not known if fracture healing, a biological process that requires extensive resorptive activity, would be compromised in patients treated with bisphosphonates. Further insight into the precise molecular and cellular mechanisms by which bone turnover is increased in OI could lead to more specific targeting of drugs, such that benefits similar to those achieved with bisphosphonate therapy could be realized without potential adverse effects. An exciting potential new therapy would be the use of osteoprotegerin (OPG), a naturally occurring soluble factor synthesized by osteoblasts, which blocks binding of Receptor Activator of NF-kB Ligand (RANKL) to osteoclast precursors and thereby inhibits osteoclastogenesis. The goals of this proposal are to: 1) use the growing oim1dim mouse, an established animal model of moderate-to-severe OI, to determine if treatment with OPG will result in improved bone properties and reduced fracture rate without compromised fracture healing. 2) determine if osteoclasts in the oimloim mice exhibit increased resorptive activity as a result of inappropriate signaling from RANKL produced by osteoblasts, or inappropriate signaling from the presence of abnormal bone mineral, and 3) determine if osteoclasts from patients with OI exhibit similar defective resorptive activity.
The specific aims of this proposal are: 1) To treat growing oim1dim mice with OPG for 3 or 6 months, and evaluate specific bone properties, including fracture number, density, geometry, mechanical strength, mineral quality and histomorphometric parameters. Fracture healing will also be evaluated by creation of a closed transverse femoral fracture in the oim1bim mice after OPG treatment. 2) To culture osteoclast precursor cells derived from oim1bim bone marrow cells on bovine bone slices either with RANKIL or with oimldim osteoblasts, and evaluate resorptive activity; To culture osteoclast precursor cells derived from oim1bim bone marrow cells with RANKIL on bone substrates prepared from either oim/bim or +/+ calvarial bone and quantitate resorptive activity. 3) To culture osteoclast precursors from human OI peripheral blood monocytes and similarly evaluate their resoprtive active. The information gained from these studies will permit design of improved therapeutic protocols so that new modalities of treatment for children and adults with OI could be developed.
Showing the most recent 10 out of 14 publications
