Role of Protein Kinase D in Age-Related Osteopenia

描述（由申请人提供）：该项目的目标是确定蛋白激酶D （PKD）是体内骨形成的主要调节因子，PKD活性的衰减导致与年龄相关的骨质减少。我们发表的和初步的数据，以及其他人的数据表明，PKD活性是体外分化和矿化成骨细胞对骨形态发生蛋白（BMPs）的反应所必需的，并且在老年动物中，对BMP-7的骨形成作用存在体外和体内抗性。最近可用的

DESCRIPTION (provided by applicant): The goal of this project is to establish that protein kinase D (PKD) is a major regulator of bone formation in vivo and that attenuation of PKD activity leads to age-related osteopenia. Our published and preliminary data, as well as that of others, indicated that PKD activity is required for the in vitro differentiation and mineralizationof osteoblasts in response to bone morphogenetic proteins (BMPs) and that in aged animals there is in vitro and in vivo resistance to the bone forming actions of BMP-7. The recent availability of mouse models with deficiency of PKD1 or PKD2 catalytic activity has allowed us to obtain preliminary in vivo data indicating that the bone mineral density of pubertal PKD1 and PKD2 deficient mice is significantly reduced compared to their age- and gender-matched littermates. We will now test whether native bone of PKD1 and PKD2 deficient mice show diminished bone mineral density, impaired bone architecture, and age-related osteopenia, compared to wild-type controls throughout the life span. We will also determine whether the reduction in bone mineral density in these PKD deficient mice is due to alternations in bone formation or in bone resorption or both. This will be accomplished using cultured osteoprogenitor cells from these PKD1 and PKD2 deficient mice. We will utilize DEXA and CT scanning in young, middle aged and old mice to determine whether: 1) Native bone of younger PKD deficient mice exhibits attenuated mineral content and density as is observed in older wild type mice, and 2) BMP-7 induced ectopic bone, whose formation is attenuated in older mice, shows reduced activation of PKD in the old wild type mice, and whether young mice deficient in PKD catalytic activity exhibit attenuated bone formation similar to that seen in older wild type mice. Successful outcomes will provide proof of principal that PKD is a critical determinant of bone remodeling in the intact animal setting, and that age related reduction in the ability of growth factors to activate PKD in vivo has major consequences for age-related osteoporosis.