Unraveling Mechanisms Driving Female-Specific Osteogenesis after Disrupting a Brain-to-Bone Circuit

摘要 雌激素是能量平衡和骨骼代谢的重要调节剂。女性花费超过1/3的时间 生活在雌激素耗尽的状态;大大增加他们患与年龄有关的骨骼疾病的风险， 骨质疏松症和骨折。我们实验室和其他人最近的研究表明， 下丘脑弓状核（ARC）中的信号传导导致女性特有的骨量升高 然而，控制这些反应的分子机制仍然未知。我假设 Esr 1 Nkx 2 -1Cre和ERaKOARC雌性小鼠ARC中ER α的缺失释放了一种体液脑依赖性的 成骨因子（BDOF），其固有地改变驻留的SSC，决定这些细胞用于成骨， 改变的SSC足以增强骨折修复和逆转骨丢失， 老年小鼠模型在本项目中，我将1）使用不稳定胫骨骨折模型来询问Esr 1 Nkx 2 -1Cre是否 女性的骨折修复能力增强2)我将使用我的新的生物测定法来测试HPLC/FPLC分级小鼠 血浆以鉴定和纯化BDOF，以及3）我将鉴定驱动成骨细胞扩增的分子信号 在雌性突变体中使用一种mu-衍生的SSC移植模型。回答这些问题对于 妇女和男子与骨骼有关的疾病的治疗方法的进步。

ABSTRACT Estrogen is a critical regulator of energy balance and skeletal metabolism. Women spend more than 1/3 of their lives in an estrogen depleted state; drastically increasing their risk for age-related bone diseases such as osteoporosis and fractures. Recent work by our lab and others demonstrates that loss of central estrogen signaling in the arcuate nucleus (ARC) of the hypothalamus results in a female-specific elevation in bone mass and strength, however molecular mechanisms that govern those responses are still unknown. I hypothesize that deletion of ERa in the ARC of Esr1Nkx2-1Cre and ERaKOARC female mice releases a humoral brain-dependent osteogenic factor (BDOF) which inherently changes resident SSCs, fating these cells for osteogenesis, and that the changed SSCs are sufficient to enhance fracture repair and reverse bone loss in osteoporotic and aged mouse models. For this project I will 1) use an unstabilized tibia fracture model to ask if Esr1Nkx2-1Cre females have enhanced fracture repair. 2) I will use my new bioassay to test HPLC/FPLC fractionated mouse plasma to identify and purify the BDOF, and 3) I will identify the molecular signals driving osteoblast expansion in female mutants using a mutant-derived SSC transplant model. Answering these questions is critical for the advancement of therapeutics for bone-related diseases in women and men.