Regulation of osteoclast biology by anion exchanger SLC4A2 in mouse and human sys

阴离子交换剂 SLC4A2 在小鼠和人类系统中对破骨细胞生物学的调节

基本信息

批准号：
8703611
负责人：
ANTONIOS O ALIPRANTIS
金额：
$ 37.44万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703611
关键词：
Acids Actins Adult Affect Age Albers-Schonberg disease Alkalinization American Anions Apoptosis Area Bicarbonates Biology Bone Diseases Bone Marrow Bone Resorption Bone Surface Bone remodeling Boston Calcified Cattle Cells Cellular biology Chloride Ion Chlorides Collaborations Complex Cytokine Receptors Cytoplasm Cytoplasmic Tail Cytoskeleton Data Defect Development Disease Drug Kinetics Environment Enzymes Family Genes Giant Cells Grant Health Health Care Costs Human Hydrochloric Acid Inequality Inflammatory Ions Knockout Mice Ligands Medical Metastatic Neoplasm to the Bone Minerals Mus Mutation Myelogenous N-terminal Osteitis Osteoblasts Osteoclasts Osteolysis Osteoporosis Pathogenesis Pathologic Peptide Hydrolases Pharmaceutical Preparations Phase Phenotype Physiology Play Population Process Publications Publishing RNA Interference Regulation Relative (related person)Reporting Research Personnel Rheumatoid Arthritis Role Signal Transduction Skeleton Staging Stress Structure TNFSF11 gene Tissues Transmembrane Domain Work apical membrane base basolateral membrane bone bone health bone loss bone mass burden of illness cell type gene function in vivo member mouse model novel osteoporosis with pathological fracture postnatal prevent seal skeletal skeletal abnormality skeletal disorder solute therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Bone is a dynamic tissue that remodels to grow, adapt to stress and maintain integrity. Two cell types control this process, the osteoblast (OB) and the osteoclast (OC), which synthesize and degrade bone, respectively. Pathologic inequality in bone remodeling favoring resorption over formation leads to diseases such as osteoporosis, rheumatoid arthritis and metastatic bone cancer. Currently, over 30 million Americans have low bone mass and nearly 1% of our population suffers from rheumatoid arthritis. The yearly health care cost burden of these diseases is immense. Currently approved therapeutics targeting OCs are inadequate, necessitating the discovery of new targets. To resorb bone, osteoclasts secrete hydrochloric acid. To prevent a reciprocal build up of cytoplasmic base, electroneutral exchange of bicarbonate for chloride occurs through an anion exchanger. The identity of this exchanger eluded identification until our recent report showing Solute carrier family 4, anion exchanger, member 2 (Slc4a2, Ae2) is absolutely required for osteoclast activity during development. In its absence, mice develop profound osteopetrosis. A recent publication has identified a nearly identical phenotype in cattle that lack SLC4A2. To date, only a handful of mutations have been identified that so dramatically curtail the ability of osteoclasts to resorb calcified tissue. Our preliminary data suggest that SCL4A2 plays an unexpected complex role in OC physiology. We have found that SLC4A2 deficiency not only prevents OCs from properly secreting acid and performing anion exchange, but also profoundly affects the organization of their cytoskeleton. Many important questions remain regarding the biology of SLC4A2 in the OC. We do not know whether SLC4A2 is important in bone remodeling beyond the developmental period or in the pathogenesis of inflammatory skeletal disease. The relative contribution of the cytoplasmic and transmembrane domains of SLC4A2 to the regulation of osteoclast biology is unknown. Moreover, whether human osteoclasts utilize SLC4A2 is undefined. Four specific aims are proposed to answer these questions: 1) Establish the OC-intrinsic role of SLC4A2 and resolve the contribution of osteopetrosis to the lethal phenotype of Slc4a2-/- mice; 2) Establish the requirement of SLC4A2 in a mouse model of inflammatory arthritis; 3) Perform a structure-function analysis of SLC4A2 in OCs and 4) Confirm a role for SLC4A2 in human OCs. I will take advantage of the unique environment in Boston to facilitate these studies. Collaborations have been established with local experts in anion exchange physiology, OC cell biology, mouse models of RA and RNA interference. By analyzing the function of a gene that so profoundly affects OC biology, this grant will advance basic understanding of skeletal remodeling, make important contributions to general cell biology and signal transduction and, most importantly, define a new target to suppress pathologic bone loss.

描述（由申请人提供）：骨骼是一种动态组织，可以重塑生长，适应压力并保持完整性。两种细胞类型控制该过程，分别合成和降解骨的破骨细胞（OB）和破骨细胞（OC）。骨骼重塑的病理不平等有利于吸收而不是形成，导致骨质疏松症，类风湿关节炎和转移性骨癌等疾病。目前，超过3000万美国人的骨骼质量低，近1％的人口患有类风湿关节炎。这些疾病的年度医疗保健成本负担是巨大的。目前批准的针对OC的治疗剂不足，因此需要发现新目标。为了吸收骨骼，破骨细胞分泌盐酸。为了防止相互构建细胞质碱，通过阴离子交换器发生碳酸氢盐的电自植物交换。这种交换器的身份避免了识别，直到我们最近的报告显示溶质载体家族4，Anion交换器，成员2（SLC4A2，AE2）是开发过程中破骨细胞活动的绝对必需的。在缺席的情况下，小鼠会出现深刻的骨质疏松症。最近的出版物已经确定了缺乏SLC4A2的牛几乎相同的表型。迄今为止，仅发现了少数突变，从而极大地削弱了破骨细胞钙化组织的能力。我们的初步数据表明，SCL4A2在OC生理学中起意想不到的复杂作用。我们发现SLC4A2缺乏不仅阻止OC适当分泌酸和进行阴离子交换，而且还深刻影响了其细胞骨架的组织。关于OC中SLC4A2的生物学仍然存在许多重要问题。我们不知道SLC4A2在发育期之后的骨头重塑中是否重要，还是炎症骨骼疾病的发病机理。 SLC4A2的细胞质和跨膜结构域对骨细胞生物学调节的相对贡献尚不清楚。此外，使用SLC4A2的人类破骨细胞是否不确定。提出了四个特定的目的来回答以下问题：1）确定SLC4A2的OC-内在作用，并解决骨质骨术对SLC4A2 - / - 小鼠的致命表型的贡献； 2）在炎症性关节炎的小鼠模型中确定SLC4A2的需求； 3）对OC中的SLC4A2进行结构功能分析，4）确认SLC4A2在人类OC中的作用。我将利用波士顿独特的环境来促进这些研究。已经与当地专家建立了阴离子交换生理学，OC细胞生物学，RA和RNA干扰的小鼠模型的合作。通过分析如此深远影响OC生物学的基因的功能，该赠款将提高对骨骼重塑的基本理解，对一般细胞生物学做出重要贡献和信号转导，最重要的是，定义了抑制病理骨损失的新目标。