Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta

成骨不全(OI)是一种遗传异质性疾病，影响着近2万名美国公民 导致骨骼脆弱的紊乱。OI患者生活在严重的慢性疼痛中，这也影响了他们的 活动水平和生活质量。双膦酸类药物目前在OI儿童的标签外使用以改善病情 增加骨量，减少骨骼畸形。然而，尽管骨量有所改善，双盲安慰剂- 对照试验没有发现接受双磷酸盐治疗的OI患者的骨折发生率降低。一个 对于这种明显的疗效缺乏的建议解释是，双膦酸盐诱导骨骼增加 质量还可以减轻疼痛，从而增加患者的活跃度。因此，正是增加的活动才是 矛盾的是，双磷酸盐治疗的OI患者的骨折速度与未治疗的患者相同。 然而，可靠地评估OI患者的疼痛和活动度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，自动化的Holeboard测试显示，在活动性和探索性方面存在显著差异 中度OI的JRT小鼠模型和野生型窝产仔之间的行为，与骨折无关。我们 现在想要确定增加骨量的治疗方法，例如通过增强 WNT信号转导和通过抑制破骨细胞活性、改善活性和增加代谢来防止分解代谢 在JRT小鼠中的探索行为，我们希望将我们的研究扩展到AGA2小鼠，一种更严重的 喂。我们还将确定阿片类止痛剂丁丙诺啡-SR是否会增加小鼠的活动和行为 OI模型，与骨折或骨量增加无关。尽管小鼠不是人类，但外设 而中枢痛觉通路在这些物种之间高度保守。此外，一群老鼠 在固定的遗传背景上有相同突变的人可以被类似地安置和处理，在 相同的年龄，一天中的时间，在测试之间的顺序和间隔一致。 这些实验的成功完成将告诉我们，影响骨量和骨量的治疗方法 骨骼特性提供了额外的好处，如增加活动和减少焦虑。如果这些额外的 好处发生在OI小鼠身上，也可能发生在OI患者身上。

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.