Control of Bone Mass by Progranulin

颗粒体蛋白前体对骨量的控制

• 批准号: 10509393
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10509393
• 关键词: Adult; Affect; Age-Related Bone Loss; Aging; Amyloid; Anabolism; Automobile Driving; Bone Diseases; Bone Formation Inhibition; Bone Marrow; Bone Marrow Transplantation; Bone Resorption; Bone Resorption Stimulation; Cell Lineage; Cells; Coupled; Cyclic AMP; Defect; Deficiency Diseases; Disease; Estrogen deficiency; Female; Fracture; GTP-Binding Proteins; Galectin 3; Gene Deletion; Gene Expression; Genes; Genetic; Genetic Suppression; In Vitro; Inflammation; Inflammatory; Injury; Innate Immune Response; Innate Immune System; Joints; K/BxN model; Knockout Mice; Knowledge; Link; Macrophage; Maintenance; Mediating; Menopause; Modeling; Mus; Musculoskeletal Diseases; Natural Immunity; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Ovariectomy; PGRN gene; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Postmenopausal Osteoporosis; Production; Reporting; Rheumatoid Arthritis; Role; Serum; Services; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Development; Skeleton; TNF gene; Testing; Therapeutic; Transplantation; Veterans; WNT Signaling Pathway; beta catenin; bone; bone erosion; bone loss; bone mass; bone turnover; cytokine; fracture risk; in vivo; interest; mouse model; negative affect; new therapeutic target; novel; osteoclastogenesis; osteogenic; prevent; progenitor; repaired; response; skeletal; therapeutic target

The maintenance of healthy bones in adults requires coordinated bone turnover where bone formation is closely coupled to bone resorption, allowing bone renewal with the maintenance of bone mass. Uncoupling of bone formation and bone resorption underlies the loss of bone mass seen in a variety of conditions including aging, the menopause, and various inflammatory disorders such as rheumatoid arthritis (RA). These disorders are generally associated with enhanced bone resorption accompanied by rates of bone formation that are inadequate for the level of resorption. Anti-resorptive therapies have been the traditional approach for treating patients with low bone mass in these conditions, but it is increasingly recognized that anabolic therapies that enhance bone formation constitute an important alternative strategy. Previous studies have identified that inhibitory G protein (Gi) signaling in osteoblast lineage cells suppresses bone formation and is an important driver of age-related bone loss in females, but the factors that are upstream of this signaling pathway are unknown. Suppression of canonical Wnt signaling in osteoblast lineage cells is also linked to reduced bone formation. The present study will use a variety of mouse models to test the hypothesis that progranulin (PGRN), an inflammation-associated factor produced by macrophages and implicated in age-related bone loss, is a critical upstream regulator of inflammatory cytokine production and that PGRN-mediated cytokine production promotes bone loss through activation of Gi signaling and suppression of canonical Wnt signaling in osteoblast lineage cells. This hypothesis will be tested in three specific aims. In Specific Aim 1, the role of PGRN in bone marrow macrophage (BMM)-regulated bone formation will be explored. To accomplish this, we will determine whether alternations in the population of BMMs accounts for promotion of bone resorption by PGRN; whether expression of PGRN reduces the pro- osteogenic activity of BMMs; and whether transplantation of BMMs from PGRN-deficient mice can protect or reverse bone loss in adult female mice. Specific Aim 2 will address the role of suppression of anabolic signaling pathways in the negative effects of PGRN on bone formation. The role of the canonical Wnt pathway will be investigated in vivo in mice with targeted deletion of Ctnnb1, the gene encoding b-catenin, and will be investigated in vitro in osteoblast lineage cells lacking expression of PGRN. The ability of PGRN to inhibit Gs/cyclic AMP signaling will be assessed in vitro in cultured osteocytes and in vivo in its ability to limit the anabolic response to intermittent PTH administration. Specific Aim 3 is a translational aim in which we will explore the role of PGRN in mediating bone loss in two disorders associated with inflammation- rheumatoid arthritis (RA) and estrogen deficiency-induced osteoporosis. We will determine whether PGRN deficient mice are protected from bone loss after ovariectomy (OVX) and from systemic bone loss and local joint erosion in the K/BxN serum transfer model of RA. The effect of PGRN deletion on the inflammatory phenotype of BBMs in response to serum transfer and OVX will also be assessed. Bone marrow transplantation studies will be carried out to determine whether PGRN-deficient BBMs can rescue the skeletal pathology associated with OVX and RA. Successful completion of the studies in this proposal will illuminate the pathogenesis of bone disease associated with inflammatory disorders such as RA and postmenopausal osteoporosis. Defining the details of this relationship will lead to the identification of new therapeutic targets for preventing or reversing bone loss in these conditions.

成人健康骨骼维持需要协调的骨转换，骨形成是 与骨吸收紧密结合，可以通过维持骨骼的骨骼更新。解偶联 骨形成和骨吸收是在各种条件下看到的骨质量损失的基础 包括衰老，更年期和各种炎症性疾病，例如类风湿关节炎（RA）。 这些疾病通常与增强的骨吸收有关，并伴有骨骼速率 对于吸收水平而言，形成不足。反应疗法是传统的 在这种情况下治疗低骨量患者的方法，但越来越多地认识到 增强骨形成的合成代谢疗法构成了重要的替代策略。以前的 研究已经确定成骨细胞谱系中的抑制性G蛋白（GI）信号抑制骨骼 形成，是女性与年龄相关的骨质损失的重要驱动力，但是上游的因素 该信号通路未知。抑制成骨细胞谱系细胞中的典型Wnt信号传导 也与减少骨形成有关。本研究将使用各种鼠标模型来测试 假设PROGRANULIN（PGRN）是由巨噬细胞和 与年龄相关的骨质流失有关，是炎症细胞因子产生的关键上游调节剂 PGRN介导的细胞因子产生通过激活GI信号传导和 在成骨细胞谱系细胞中抑制规范Wnt信号传导。该假设将在三个 具体目标。在特定的目标1中，PGRN在骨髓巨噬细胞（BMM）调节的骨骼中的作用 将探索编队。为此，我们将确定人口中的交替是否 BMMS解释了PGRN促进骨吸收的； PGRN的表达是否会降低pro- BMM的成骨活性；以及从缺乏PGRN的小鼠中BMM的移植是否可以保护 或成年雌性小鼠的骨质流失。具体目标2将解决抑制合成代谢的作用 PGRN对骨形成的负面影响的信号通路。规范Wnt的角色 途径将在具有靶向缺失的CTNNB1靶向缺失的小鼠中研究，该基因编码B-catenin，b-catenin， 并将在缺乏PGRN表达的成骨细胞细胞中进行体外研究。 PGRN的能力 在培养的骨细胞和体内，将评估抑制GS/环状AMP信号传导的能力 限制对间歇性PTH给药的合成代谢响应。特定目标3是转化目的 我们将探讨PGRN在介导与炎症相关的两种疾病中的骨质流失中的作用 - 类风湿关节炎（RA）和雌激素缺乏诱导的骨质疏松症。我们将确定PGRN是否 卵巢切除术（OVX）和全身骨质流失和 RA的K/BXN血清转移模型中的局部关节侵蚀。 PGRN删除对 还将评估BBMS对血清转移和OVX的炎症表型。骨 将进行骨髓移植研究，以确定缺乏PGRN的BBM是否可以营救 与OVX和RA相关的骨骼病理学。在该提案中成功完成研究 将阐明与RA和RA和 绝经后骨质疏松症。定义这种关系的细节将导致识别新的 在这些条件下预防或逆转骨质流失的治疗靶标。