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，在 800万50岁以上的女性和200万50岁以上的男性患有骨质疏松症。另有5100万妇女和35 百万男性骨质疏松这意味着这一人群中骨折的风险更高， 妇女和四分之一的男子预计将遭受低骨量相关骨折。骨质疏松性骨折 造成有害后果，包括增加住院率和死亡率。据估计， 每个人都会在髋骨骨折后一年内死亡。尽管有抗吸收疗法， 减少骨折率，他们的处方和使用显着下降，由于担心极其罕见，但 严重不良事件。这造成了一个治疗差距，威胁到数百万人的生活质量。 这对我们的医疗保健系统和经济构成了巨大的挑战。它还强调了 需要更好地了解破骨细胞的形成和功能。这五年申请的目标是 确定蛋白磷酸酶Phlpp 1在破骨细胞生成和骨密度中的作用， Phlpp 1调节Csf 1 r（c-fms）表达和破骨细胞生成所需的表观遗传机制。的 五年的交付成果是：1）破骨细胞祖细胞中Phlpp 1功能的定义，2） Phlpp 1影响M-CSF反应性、Csfr 1表达的胞浆功能的表征 和破骨细胞功能; 3）测定影响Csfr 1的Phlpp 1的核功能 转录和破骨细胞生成。这项工作将增加我们对Phlpp 1和相关的 影响骨密度的通路。

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.