Adenosine A2B Receptor in Bone Health and Osteoporosis

腺苷 A2B 受体在骨骼健康和骨质疏松症中的作用

基本信息

批准号：
9551206
负责人：
Shyni Varghese
金额：
$ 48.17万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9551206
关键词：
Address Adenosine A2B Receptor Affect Age Alendronate Animal Model Biomechanics Bone Marrow Bone Resorption Bone Tissue Bone Transplantation Cell membrane Cells Cues Degenerative Disorder Disease Disease Progression Dose Dual-Energy X-Ray Absorptiometry Environment Enzyme-Linked Immunosorbent Assay Equilibrium Estradiol Fracture G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Goals Hematopoietic Homeostasis Human Implant In Vitro Intervention Lead Mesenchymal Stem Cells Metabolic Bone Diseases Minerals Modeling Molecular Mus Organ Osteoblasts Osteoclasts Osteogenesis Osteoporosis Osteoporotic Outcome Pathogenesis Pathologic Pathway interactions Pharmaceutical Preparations Pharmacology Play Population Postmenopausal Osteoporosis Postmenopause Protein Array Public Health Research Role Signal Pathway Signal Transduction Small Interfering RNA Source Staining method Stains Technology Testing Therapeutic Time Tissue Engineering Tissue Model Transplanted tissue United States Woman animal tissue bisphosphonate bone bone cell bone engineering bone health bone loss bone mass drug development drug discovery fracture risk humanized mouse improved outcome in vivo Model lipid biosynthesis long bone macrophage men mouse model new therapeutic target novel strategies novel therapeutic intervention novel therapeutics osteoblast differentiation osteogenic osteoporotic bone overexpression peripheral blood preclinical study prevent programs restoration scaffold stem cell differentiation success therapeutic target tissue degeneration tomography

Address Adenosine A2B Receptor Affect Age Alendronate Animal Model Biomechanics Bone Marrow Bone Resorption Bone Tissue Bone Transplantation Cell membrane Cells Cues Degenerative Disorder Disease Disease Progression Dose Dual-Energy X-Ray Absorptiometry Environment Enzyme-Linked Immunosorbent Assay Equilibrium Estradiol Fracture G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Goals Hematopoietic Homeostasis Human Implant In Vitro Intervention Lead Mesenchymal Stem Cells Metabolic Bone Diseases Minerals Modeling Molecular Mus Organ Osteoblasts Osteoclasts Osteogenesis Osteoporosis Osteoporotic Outcome Pathogenesis Pathologic Pathway interactions Pharmaceutical Preparations Pharmacology Play Population Postmenopausal Osteoporosis Postmenopause Protein Array Public Health Research Role Signal Pathway Signal Transduction Small Interfering RNA Source Staining method Stains Technology Testing Therapeutic Time Tissue Engineering Tissue Model Transplanted tissue United States Woman animal tissue bisphosphonate bone bone cell bone engineering bone health bone loss bone mass drug development drug discovery fracture risk humanized mouse improved outcome in vivo Model lipid biosynthesis long bone macrophage men mouse model new therapeutic target novel strategies novel therapeutic intervention novel therapeutics osteoblast differentiation osteogenic osteoporotic bone overexpression peripheral blood preclinical study prevent programs restoration scaffold stem cell differentiation success therapeutic target tissue degeneration tomography

展开

项目摘要

ABSTRACT Bone is a highly dynamic organ that undergoes continuous remodeling and maintains a balance between bone formation and resorption. Bone cells, osteoblasts, which contribute to new bone formation, and osteoclasts, which resorb bone tissue, act in concert to maintain bone homeostasis. A perturbation to these highly coordinated cellular activities often results in bone metabolic and degenerative diseases such as osteoporosis. Osteoporosis is a disease of dysregulated bone homeostasis characterized by low bone mass and a significant increase in fracture risk. This pathological condition represents a major public health problem with osteoporosis-associated fractures occurring in an estimated one in two women and one in four men age 50 and older in the United States alone. We recently showed adenosine A2B receptor (ADORA2B), a G-protein coupled receptor on the cell membrane, plays an important role during osteogenic and osteoclastic differentiation of MSCs and macrophages respectively. These findings along with our ongoing studies highlight the potential of ADORA2B as a novel therapeutic target for the treatment of diseases characterized by low bone mass such as osteoporosis. Unlike most of the currently available drugs that only slow down disease progression but do not promote bone formation, activation of ADORA2B offers a therapy with dual function that promotes osteoblast differentiation (bone formation) while inhibiting osteoclast activity (bone resorption). By employing a number of in vitro and in vivo models, we will: (1) study the role of ADORA2B on osteoblast and osteoclast differentiation and unearth the underlying intracellular signaling mechanism, (2) determine the therapeutic potential of targeting ADORA2B to treat postmenopausal osteoporosis by using an ovariectomized mouse model, and (3) establish humanized osteoporotic bone in animal models. Targeting ADORA2B to treat bone loss is not limited to the study of osteoporosis but has broad applications that can be extended to treatment of various bone metabolic diseases. The humanized bone tissue models could lead to new enabling technologies for drug discovery and overcome species-specific discrepant findings in preclinical studies.

抽象的骨骼是一种高度动态的器官，经过连续重塑并保持骨头之间的平衡形成和吸收。骨细胞，成骨细胞，有助于新的骨形成和破骨细胞，吸收骨组织，共同起作用以维持骨骼稳态。对这些高度扰动协调的细胞活性通常会导致骨代谢和退化性疾病，例如骨质疏松症。骨质疏松症是一种失调的骨骼稳态失调的疾病，其特征是骨骼低，显着裂缝风险增加。这种病理状况代表了一个主要的公共卫生问题骨质疏松相关的骨折发生在估计的两分之一的女性中，四分之一的男性50岁仅在美国就年龄较大。我们最近显示了腺苷A2b受体（Adora2b），一种G蛋白细胞膜上的耦合受体，在成骨和整骨术中起重要作用 MSC和巨噬细胞的分化。这些发现以及我们正在进行的研究突出显示 Adora2b作为以低疾病为特征的疾病治疗的新型治疗靶标的潜力骨骼质量，例如骨质疏松症。与大多数仅放慢疾病的当前可用药物不同进展但不促进骨形成，adora2b的激活提供了具有双重功能的疗法促进成骨细胞分化（骨形成），同时抑制破骨细胞活性（骨吸收）。经过使用多种体外和体内模型，我们将：（1）研究adora2b在成骨细胞和破骨细胞分化和出土的细胞内信号传导机制，（2）确定靶向adora2b的治疗潜力通过使用卵巢切除术治疗绝经后骨质疏松症小鼠模型和（3）在动物模型中建立人性化的骨质疏松骨。针对adora2b治疗骨质流失不仅限于骨质疏松症的研究，但具有广泛的应用，可以扩展到治疗各种骨代谢疾病。人性化的骨组织模型可能导致新的启用临床前研究中的药物发现和克服物种特异性差异的发现。