Functions of the PH-Domain Leucine Rich Protein Phosphatase (Phlpp)1 in Osteoclasts

摘要 骨质疏松症是发达国家发病率和死亡率的重要原因。在美国，结束了 800万50岁及以上的女性和200万男性患有骨质疏松症。另有5100万名女性和35名 有数百万男性患有骨质疏松症。这转化为该人群中更高的骨折风险，有一半的人 女性和四分之一的男性预计会遭受与低骨量相关的骨折。骨质疏松性骨折 造成有害后果，包括增加住院和死亡率。估计有25%的人 个人将在髋部骨折后一年内死亡。尽管有抗吸收疗法可用， 降低骨折发生率，他们的处方和使用已经显著下降，因为担心极其罕见但 严重的不良事件。这造成了一个治疗缺口，威胁到数百万人的生活质量 并对我们的医疗体系和经济构成了巨大的挑战。它还突出了 需要更好地了解破骨细胞的形成和功能。这项为期五年的申请的目标是 确定蛋白磷酸酶PHLPP1在破骨细胞形成和骨密度中的作用，并确定 PHLPP1调节CSF1R(c-FMS)表达和破骨细胞生成所需的表观遗传学机制。这个 五年的交付成果是：1)PHLPP1在破骨细胞前体细胞中的功能定义，2) 影响M-CSF反应性和Csfr1表达的PHLPP1的胞浆功能特征 和破骨细胞功能，以及3)影响Csfr1的PHLPP1核功能的测定 转录和破骨细胞发生。这项工作将增加我们对PHLPP1和关联的理解 途径会影响骨密度。

Abstract Osteoporosis is a significant cause of morbidity and mortality in developed countries. In the United States, over 8 million women and 2 million men age 50 and above have osteoporosis. Another 51 million women and 35 million men have osteopenia. This translates into a higher risk of fracture within this population, with half of all women and one quarter of men projected to suffer a low bone mass-related fracture. Osteoporotic fractures impart deleterious consequences, including increased hospitalization and mortality. An estimated 25% of individuals will die within one year of a hip fracture. Despite the availability of anti-resorptive therapies that decrease fracture rates, their prescription and use have declined significantly due to fears of extremely rare but serious adverse events. This has created a treatment gap that threatens the quality of life of millions of Americans and poses a tremendous challenge to our healthcare systems and economy. It also highlights the need to better understand osteoclast formation and function. The goal of this five-year application is to determine the role of the protein phosphatase Phlpp1 in osteoclastogenesis and bone density and to define the epigenetic mechanisms required for Phlpp1 to modulate Csf1r (c-fms) expression and osteoclastogenesis. The five-year deliverables are: 1) definition of the functions of Phlpp1 in osteoclast progenitor cells, 2) characterization of the cytosolic functions of Phlpp1 that influence M-CSF responsiveness, Csfr1 expression and osteoclast function, and 3) determination of the nuclear functions of Phlpp1 that influence Csfr1 transcription and osteoclastogenesis. This work will increase our understanding of how Phlpp1 and associated pathways affect bone density.