Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta

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Osteogenesis Imperfecta (OI), which affects nearly 20,000 US citizens, is a genetically heterogeneous disorder that causes skeletal fragility. Patients with OI live with significant chronic pain, which also affects their level of activity and quality of life. Bisphosphonates are currently used off-label in children with OI to improve bone mass and reduce skeletal deformity. Yet, despite improvements in bone mass, double-blind placebo- control trials have not found reduced fracture rates in OI patients who have received bisphosphonates. A suggested explanation for this apparent lack of efficacy is that bisphosphonate-induced increases in bone mass also reduce pain and as a consequence increase patient activity. Thus, it is the increased activity that paradoxically causes bisphosphonate-treated OI patients to fracture at the same rate as untreated patients. However, the ability to robustly assess pain and activity in OI patients is limited by several factors. OI patients have a range of clinical severity that is influenced by their specific mutation, genetic background, age, and environment. In addition, non-physiological factors such as cognitive, behavioral, and spiritual components affect how OI patients self-report pain, activity, and quality of life. We found that the automated Holeboard assay reveals significant differences in activity and exploratory behavior between the Jrt mouse model of moderate OI and wild-type littermates, independent of fracture. We now want to determine if therapies that increase bone mass, such as promoting bone anabolism by enhancing Wnt signaling and preventing catabolism by inhibiting osteoclast activity, improve activity and increase exploratory behavior in the Jrt mice, and we want to extend our studies to AGA2 mice, a more severe model of OI. We will also determine if the opioid analgesic Buprenorphine-SR increases activity and behavior in mouse models of OI, independent of fracture or increasing bone mass. Even though mice are not humans, peripheral and central pain perception pathways are highly conserved between these species. Moreover, cohorts of mice with the same mutation on a fixed genetic background can be housed and handled similarly, evaluated at the same age, time of day, and in a consistent order and spacing between tests. Successful completion of these experiments will inform us whether therapies that affect bone mass and bone properties provide additional benefits, such as increased activity and reduced anxiety. If these additional benefits occur in OI mice, they are likely to occur in OI patients as well.