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G Protein Signaling in Osteoblasts

成骨细胞中的 G 蛋白信号转导

基本信息

批准号：
8413401
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
项目类别：
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/8413401
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

项目摘要

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）：