Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta

影响近20，000名美国公民的成骨不全症（OI）是一种遗传异质性疾病， 导致骨骼脆弱的疾病。OI患者生活在严重的慢性疼痛中，这也影响了他们的生活质量。 活动水平和生活质量。双膦酸盐目前在OI儿童中超说明书使用， 骨量和减少骨骼畸形。然而，尽管骨质量有所改善，双盲安慰剂- 对照试验没有发现接受双膦酸盐治疗的OI患者骨折率降低。一 对这种明显缺乏疗效的解释是双膦酸盐诱导的骨密度增加， 肿块还减少疼痛，并因此增加患者活动。因此，正是增加的活动， 矛盾的是，双膦酸盐治疗的OI患者骨折的发生率与未治疗的患者相同。 然而，稳健评估OI患者疼痛和活动的能力受到几个因素的限制。OI患者 具有一系列临床严重程度，受其特定突变、遗传背景、年龄和 环境此外，非生理因素，如认知，行为和精神成分 影响OI患者自我报告疼痛、活动和生活质量的方式。 我们发现，自动化孔板试验揭示了活性和探索性的显着差异， 中度OI的Jrt小鼠模型和野生型同窝小鼠之间的行为，与骨折无关。我们 现在想确定增加骨量的疗法，如通过增强 通过抑制破骨细胞活性、提高活性和增加Wnt信号传导而预防骨钙素 我们希望将我们的研究扩展到AGA2小鼠，这是一种更严重的 喂我们还将确定阿片类镇痛药丁丙诺啡-SR是否增加小鼠的活动和行为 OI模型，与骨折或骨量增加无关。尽管老鼠不是人类， 并且中枢疼痛感知通路在这些物种之间高度保守。此外， 在固定的遗传背景上具有相同突变的动物可以类似地进行饲养和处理， 相同的年龄、一天中的时间，以及测试之间的一致顺序和间隔。 这些实验的成功完成将告诉我们，影响骨量和 骨骼特性提供额外的益处，例如增加活动和减少焦虑。如果这些额外的 虽然这些益处发生在OI小鼠中，但它们也可能发生在OI患者中。

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.