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

• 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
• 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

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.

摘要 骨是一个高度动态的器官，它经历持续的重塑，并保持骨与骨之间的平衡。 形成和再吸收。骨细胞，成骨细胞，有助于新骨形成，破骨细胞， 其再吸收骨组织，协同作用以维持骨稳态。对这些高度 协调的细胞活动经常导致骨代谢和退行性疾病如骨质疏松症。 骨质疏松症是一种骨稳态失调的疾病，其特征在于低骨量和显著的 骨折风险增加。这种病理状况是一个重大的公共卫生问题， 在50岁的女性中，估计每两名女性中就有一名，每四名男性中就有一名发生骨质疏松相关骨折。 仅在美国，我们最近发现腺苷A2 B受体（ADORA 2B），一种G蛋白， 细胞膜上的一种偶联受体，在成骨和骨破坏过程中起重要作用 分别诱导MSC和巨噬细胞分化。这些发现沿着我们正在进行的研究， AD 0 RA 2B作为用于治疗以低表达为特征的疾病的新型治疗靶点的潜力 骨质疏松症等。不像大多数目前可用的药物， 虽然ADORA 2B的活化不促进骨形成，但ADORA 2B的活化提供了具有双重功能的治疗， 促进成骨细胞分化（骨形成），同时抑制破骨细胞活性（骨吸收）。通过 本研究采用多种体内外模型，主要研究：（1）ADORA 2B对成骨细胞的作用， 破骨细胞的分化和发掘潜在的细胞内信号传导机制，（2）确定 靶向ADORA 2B治疗绝经后骨质疏松症的治疗潜力 小鼠模型;（3）建立人源化骨质疏松动物模型。靶向ADORA 2B治疗 骨丢失不限于骨质疏松症的研究， 治疗各种骨代谢疾病。人源化骨组织模型可能会导致新的 这些技术用于药物发现，并克服临床前研究中物种特异性的不一致发现。