Proteoglycan-4:A novel protein regulating skeletal actions of parathyroid hormone

描述（由申请人提供）：间歇性甲状旁腺激素（PTH）（1-34）是目前唯一被批准用于治疗骨质疏松症的合成代谢药物，正在积极进行临床研究，用于治疗口腔和其他骨骼部位的局限性骨缺损。研究将促甲状旁腺激素的合成代谢作用归因于成骨细胞中超越直接促甲状旁腺激素信号传导的机制。一个不断发展的理论是，居住在骨髓环境中的造血细胞介导甲状旁腺激素的合成代谢。有趣的是，PTH信号调节支持造血干细胞（hsc）和巨核细胞的基因表达。造血干细胞和巨核细胞都是促甲状旁腺激素合成代谢作用的强有力的候选调节因子。蛋白聚糖-4 （prg4）是在项目实验室发现的一种新的甲状旁腺激素应答基因。Prg4蛋白产物的作用与关节保护、HSC扩增和巨核生成有关。prg4的功能缺失突变导致camptodacy关节病- cocovera -心包炎综合征的骨质减少和关节炎状况。prg4作为骨重塑和甲状旁腺激素合成代谢的介质的作用尚不清楚，项目实验室的初步数据支持其在甲状旁腺激素合成代谢中的作用。两个特定的目标将优化强有力的体外和体内策略，这些策略建立在使用prg4缺陷小鼠的基础上，以研究蛋白多糖-4在骨骼合成代谢和造血中介导甲状旁腺激素作用的总体假设。第一个具体目标是阐明蛋白多糖-4在成骨细胞形成中的内在作用，第二个目标是确定蛋白多糖-4在甲状旁腺激素合成代谢中的作用。原代骨髓基质细胞培养将用于体外成骨细胞形成研究。一项体内间歇性PTH研究将进行，以分析蛋白聚糖-4对造血（HSC扩增和巨核生成）、骨重塑和PTH骨骼作用的影响。体外PTH细胞扩增模型将用于进一步阐明蛋白多糖-4在造血和基质细胞增殖、分化和凋亡中的作用。这些研究将确定蛋白多糖-4在骨重塑和甲状旁腺激素作用中的作用。除了提高我们对PTH在骨中的作用的理解外，拟议的F30奖学金研究培训计划将为Chad Novince先生提供强大的基础-转化科学研究培训经验，Chad Novince先生是一名六年DDS/PhD联合候选人。Novince先生是一位有抱负的牙科科学家，他的研究兴趣集中在研究造血细胞作为甲状旁腺激素合成代谢作用的潜在介质。F30奖学金将支持Novince先生的研究，调查蛋白多糖-4在甲状旁腺激素骨骼活动中的作用，并促进他的职业发展。

DESCRIPTION (provided by applicant): Intermittent parathyroid hormone (PTH) (1-34) is currently the only anabolic agent approved for the treatment of osteoporosis, and is actively under clinical investigation to treat localized osseous defects in the oral cavity and other skeletal sites. Studies have attributed PTH anabolic actions to mechanisms that extend beyond direct PTH signaling in osteoblastic cells. An evolving theory is that hematopoietic cells residing in the bone marrow environment mediate PTH anabolism. Of interest, PTH signaling regulates the expression of genes which support both hematopoietic stem cells (HSCs) and megakaryocytes. Both HSCs and megakaryocytes are strong candidate regulators of PTH anabolic actions. Proteoglycan-4 (prg4) is a novel PTH responsive gene that was identified in the project laboratory. Prg4 protein product actions have been implicated in articular joint protection, HSC expansion, and megakaryopoiesis. Loss-of-function mutations in prg4 result in the osteopenic and arthritic condition of camptodactyly-arthropathy-coxa vera-pericarditis syndrome. The role of prg4 as a mediator of bone remodeling and PTH anabolism is unknown with preliminary data from the project laboratory supporting its role in anabolic actions of PTH. Two specific aims will optimize strong in vitro and in vivo strategies built upon the use of prg4 deficient mice to investigate the overall hypothesis that proteoglycan-4 mediates PTH actions in skeletal anabolism and hematopoiesis. The first specific aim will elucidate the intrinsic role of proteoglycan4 in osteoblastogenesis and the second aim will determine the role of proteoglycan-4 in anabolic actions of PTH. Primary bone marrow stromal cell cultures will be utilized for in vitro osteoblastogenesis studies. An in vivo intermittent PTH study will be carried out to analyze the impact of proteoglycan-4 in hematopoiesis (HSC expansion and megakaryopoiesis), bone remodeling, and PTH skeletal actions. An ex vivo PTH cell expansion model will be used to further elucidate the role of proteoglycan-4 in hematopoietic and stromal cell proliferation, differentiation, and apoptosis. These studies will identify the role of proteoglycan-4 in bone remodeling and PTH actions. In addition to improving our understanding of actions of PTH in bone, the proposed F30 fellowship research training plan will provide a strong basic-translational science research training experience for Mr. Chad Novince, a 6th year joint DDS/PhD candidate. Mr. Novince is an aspiring dental scientist whose research interests are focused in the investigation of hematopoietic cells as potential mediators of PTH anabolic actions. The F30 fellowship will support Mr. Novince's research studies investigating the role of proteoglycan-4 in PTH skeletal actions, as well as enhancing his career development. PUBLIC HEALTH RELEVANCE: Parathyroid hormone (PTH) is currently the only bone forming therapeutic agent approved to treat osteoporosis (condition of decreased bone mass). The proposed research will delineate the role of a novel protein called proteoglycan-4 as a mediator of the bone forming capacity of PTH. A more thorough understanding of PTH bone forming actions will optimize its clinical potential, supporting its use for localized bone defects which afflict the oral-facial region (arising from periodontal/gum disease, fractures, cancer) and other skeletal sites.