G Protein Signaling in Osteoblasts

成骨细胞中的 G 蛋白信号转导

• 批准号: 8246342
• 负责人: Robert Nissenson
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246342
• 关键词: Address; Age; Age-Related Bone Loss; Aging; Anabolic Agents; Appearance; Bone Growth; Bone Resorption; Catalytic Domain; Cell Lineage; Cells; Commit; Contracts; Cues; Development; Effectiveness; Elderly; Elements; Employee Strikes; Engineering; Environment; Event; FDA approved; Failure; Female; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Genetic; Glucocorticoids; Goals; Growth Factor; Heterotrimeric GTP-Binding Proteins; Homeostasis; Hormones; Human; In Vitro; Knowledge; Laboratories; Life; Ligands; Link; Marrow; Methods; Molecular; Mus; Osteoblasts; Osteogenesis; Osteopenia; Osteoporosis; Parathyroid gland; Pathway interactions; Patients; Pertussis Toxin; Physiology; Play; Population; Process; Production; Property; Prostaglandins E; Research Design; Risk Factors; Role; Signal Pathway; Signal Transduction; Smoking; Testing; Transgenic Mice; Veterans; Woman; age related; alcoholism therapy; bone; bone loss; bone mass; bone strength; bone turnover; computerized data processing; design; extracellular; high risk; improved; in vivo; in vivo Model; insight; men; mineralization; osteoblast differentiation; osteoprogenitor cell; paracrine; prevent; programs; receptor; response; restoration; skeletal; substantia spongiosa; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Cells in the osteoblast lineage are crucial for controlling bone formation and bone resorption throughout life. An in-depth understanding of how signaling processes within osteoblast-lineage cells are linked to bone formation and bone resorption is essential to provide new insights into skeletal physiology and to open up new avenues for osteoporosis therapy. In this regard, the G protein signaling pathway is crucial in that the only FDA-approved anabolic treatment for osteoporosis is intermittent parathyroid hormone which activates two G proteins- Gs and Gq- through a G protein coupled receptor (GPCR) in osteoblasts. Previous studies have focused largely on the role of Gs signaling, and little is known about the function of other osteoblast G protein pathways such as Gi and Gq. It is vital that we increase our understanding of how specific G protein signals in osteoblasts are linked to bone formation and bone resorption, and to define their pathophysiological significance. The complexity of the skeletal environment required for normal bone formation and turnover make it necessary to use in vivo models to address these critical issues. Our laboratory has established the utility of an approach to dissect the role of specific signaling pathways using transgenic mice expressing engineered GPCRs termed RASSLs (Receptors Activated Solely by Synthetic Ligands). Our results so far demonstrate that activation of the Gs signaling pathway in mature osteoblasts results in a massive increase in the formation of trabecular bone with a marked reduction in marrow elements and erosion of the cortex. By contract, activation of the Gi signaling pathway in mature osteoblasts results in trabecular osteopenia due to decreased rates of bone formation. Recently, we have developed a method to block endogenous Gi signaling in osteoblasts in vivo using the targeted expression of the catalytic subunit of pertussis toxin. In female mice, blockade of osteoblast Gi signaling results in increased trabecular bone formation during bone growth, and completely prevents age-related trabecular bone loss. These exciting findings indicate that endogenous Gi signaling in osteoblasts negatively regulates bone formation, and suggest that this pathway is an important contributor to age-related bone loss. In the present proposal, we will extend these observations and probe their pathophysiological relevance. Specifically, we will: 1) determine the pathophysiological importance of osteoblast Gi signaling in age-related bone loss, and assess whether osteoblast Gi signaling limits the effectiveness of PTH as an anabolic agent; 2) identify the mechanisms whereby osteoblast Gi signaling negatively regulates bone formation; and 3) determine the role of Gq signaling in mature OBs in regulating skeletal homeostasis. The knowledge gained from these studies will provide new insights into the control of osteoblastic bone formation, and these will be valuable in the design and development of improved anabolic therapies for osteoporosis.

描述（由申请人提供）： 成骨细胞谱系中的细胞在整个生命过程中对控制骨形成和骨吸收至关重要。深入了解成骨细胞系细胞内的信号传导过程如何与骨形成和骨吸收相关，对于提供骨骼生理学的新见解和开辟骨质疏松症治疗的新途径至关重要。在这方面，G蛋白信号传导途径是至关重要的，因为唯一FDA批准的骨质疏松症的合成代谢治疗是间歇性甲状旁腺激素，其通过成骨细胞中的G蛋白偶联受体（GPCR）激活两种G蛋白- Gs和Gq。以前的研究主要集中在Gs信号通路的作用上，而对其他成骨细胞G蛋白通路如Gi和Gq的功能知之甚少。这是至关重要的，我们增加了我们的理解，如何特定的G蛋白信号在成骨细胞与骨形成和骨吸收，并确定其病理生理意义。正常骨形成和转换所需的骨骼环境的复杂性使得有必要使用体内模型来解决这些关键问题。我们的实验室已经建立了一种方法的实用性，使用转基因小鼠表达被称为RASSL（仅由合成配体激活的受体）的工程GPCR来剖析特定信号通路的作用。到目前为止，我们的研究结果表明，在成熟的成骨细胞中Gs信号通路的激活导致骨小梁形成的大量增加，骨髓元素的显着减少和皮质的侵蚀。相反，成熟成骨细胞中Gi信号通路的激活由于骨形成速率降低而导致小梁骨质减少。最近，我们已经开发了一种方法来阻止内源性Gi信号在成骨细胞在体内使用百日咳毒素的催化亚基的靶向表达。在雌性小鼠中，成骨细胞Gi信号传导的阻断导致骨生长期间骨小梁形成增加，并且完全防止年龄相关的骨小梁损失。这些令人兴奋的发现表明，成骨细胞中的内源性Gi信号负调控骨形成，并表明该途径是年龄相关性骨丢失的重要贡献者。在本建议中，我们将扩展这些观察，并探讨其病理生理相关性。具体而言，我们将：1）确定成骨细胞GI信号在年龄相关骨质流失中的病理生理重要性，并评估成骨细胞GI信号是否限制了PTH作为合成代谢剂的有效性; 2）确定成骨细胞GI信号负调节骨形成的机制;和3）确定成熟OB中Gq信号在调节骨骼动态平衡中的作用。从这些研究中获得的知识将为成骨细胞骨形成的控制提供新的见解，这些将在骨质疏松症的改进合成代谢疗法的设计和开发中具有价值。