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.

成年人保持健康的骨骼需要协调的骨转换，在那里骨形成 与骨吸收紧密结合，在保持骨量的同时促进骨骼更新。解耦 骨形成和骨吸收是各种情况下骨量丢失的基础。 包括衰老、更年期和各种炎症性疾病，如类风湿性关节炎(RA)。 这些疾病通常与骨吸收增强有关，并伴有骨率。 与吸收程度不相称的地层。抗再吸收疗法一直是传统的 治疗这些情况下的低骨量患者的方法，但越来越多的人认识到 促进骨形成的合成代谢疗法是一种重要的替代策略。上一首 研究证实，成骨细胞系细胞中抑制性G蛋白(GI)信号转导抑制骨 形成，是女性年龄相关骨丢失的重要驱动因素，但上游因素 这一信号通路的具体结构尚不清楚。成骨细胞系细胞中规范Wnt信号的抑制 也与骨骼形成减少有关。本研究将使用各种小鼠模型来测试 原颗粒蛋白(PGRN)，一种由巨噬细胞和 与年龄相关的骨丢失有关，是炎性细胞因子产生的关键上游调节因子 PGRN介导的细胞因子的产生通过激活GI信号转导通路促进骨丢失 成骨细胞系细胞中规范的Wnt信号的抑制。这一假设将在三年内得到检验 明确的目标。在特定目标1中，PGRN在骨髓巨噬细胞(BMM)调节的骨中的作用 将探索编队。为了实现这一点，我们将确定人口数量的变化是否 BMMS参与了PGRN促进骨吸收的作用；PGRN的表达是否降低了促骨吸收活性。 骨髓基质细胞的成骨活性以及移植PGRN缺陷小鼠的骨髓基质细胞是否具有保护作用 或逆转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 前列腺素RN对骨形成负面影响的信号转导途径。规范的WNT的作用 靶向缺失编码b-连环蛋白的CTNNB1基因的小鼠体内将研究这一途径。 并将在体外研究缺乏PGRN表达的成骨细胞系细胞。PGRN的能力 抑制Gs/cAMP信号通路的能力将在体外培养的骨细胞和体内评估其能力 限制甲状旁腺素间歇给药的合成代谢反应。具体目标3是一个翻译目标，在这个目标中 我们将探索PGRN在两种与炎症相关的疾病中介导骨丢失的作用- 类风湿关节炎(RA)和雌激素缺乏导致的骨质疏松症。我们将确定PGRN是否 缺陷小鼠在卵巢切除(OVX)后防止骨丢失，并防止全身骨丢失和 类风湿关节炎K/BxN血清转移模型的局部关节侵蚀。PGRN基因缺失对小鼠血管紧张素转换酶活性的影响 还将评估骨髓基质细胞对血清转移和卵巢切除的反应的炎症表型。骨 将进行骨髓移植研究，以确定PGRN缺陷的骨髓干细胞是否可以挽救 与OVX和RA相关的骨骼病理。成功完成本建议书中的研究 将阐明与炎症性疾病相关的骨病的发病机制，如类风湿关节炎和 绝经后骨质疏松症。定义这种关系的细节将导致确定新的 在这些情况下预防或逆转骨丢失的治疗靶点。