Immune Regulation of Bone Homeostasis

骨稳态的免疫调节

• 批准号: 7680569
• 负责人: Mervyn Neale Weitzmann
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680569
• 关键词: Ablation; Accounting; Address; Adverse effects; Age; Aging; Antibodies; Autoimmune Diseases; Autoimmune Process; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Bone Density; Bone Diseases; Bone Marrow; Bone Marrow Transplantation; Bone Resorption; CD40 Ligand; CD8B1 gene; CTLA4 gene; CTLA4-Ig; Cell Lineage; Cells; Clinical; Complication; Crohn' s disease; Cytokine Receptors; Data; Disease; Expenditure; Female; Fracture; Functional disorder; General Population; Health; Health Care Costs; Healthcare; Hip Fractures; Homeostasis; Human; Immune; Immune system; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; Investigation; Knockout Mice; Lead; Long-Term Effects; Lymphocyte; Malignant Neoplasms; Mediating; Medical; Modeling; Modification; Monitor; Morbidity - disease rate; Multiple Sclerosis; Mus; Operative Surgical Procedures; Organ; Organ Transplantation; Osteoblasts; Osteoclasts; Osteoporosis; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Population; Production; Psoriasis; Psoriatic Arthritis; Refractory; Regulation; Rheumatoid Arthritis; Risk; Role; Signal Transduction; Skeleton; Societies; Solid; Source; Stromal Cells; Structure; Systemic Lupus Erythematosus; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF5 gene; TNFSF11 gene; Therapeutic; Therapeutic Agents; Tumor necrosis factor receptor 11b; Veterans; aged; base; bone; bone turnover; cell type; design; immune function; in vivo; indexing; inhibitor/antagonist; loss of function; male; mortality; novel therapeutics; progenitor; public health relevance; receptor; reconstitution; rituximab; skeletal; standard of care; tositumomab; young adult

DESCRIPTION (provided by applicant): Bone fractures resulting from osteoporosis lead to significant health costs, morbidity, loss of mobility, and often mortality in aged individuals. The bone destruction that drives osteoporosis is mediated by osteoclasts (OCs), bone resorbing cells that form under the influence of the key osteoclastogenic cytokine Receptor- Activator of NF-:B (RANKL). RANKL activity is moderated by its physiological decoy receptor osteoprotegerin (OPG). Historically OPG production has always been associated with osteoblast-lineage cells. However, recently we found that in mice B cells are a critical additional source of OPG in vivo, and that B cell OPG production is regulated by costimulatory signals such as CD40 Ligand (CD40L) derived from T cells. Furthermore, B cell OPG production is dramatically upregulated in aged mice in the face of declining osteoblast OPG production. We hypothesize that "Lymphocytes, through B cell OPG production, and modulated by T cell costimulation, are critical regulators of basal bone homeostasis in young mice and mitigate in part, the enhanced bone resorption associated with aging". Novel therapeutic agents that modulate immune function are under intense investigation for treatment of numerous autoimmune and inflammatory diseases, and as anti-rejection agents in bone marrow and solid organ transplantation. The long term effects of these agents on the skeleton are unknown however, our preliminary studies suggest that an unforeseen consequence of immunomodulatory therapies may be to promote osteoporosis by perturbing B cell OPG production. To ratify and extend our preliminary findings and to explore the potential clinical implications thereof, we propose to characterize the role of T cells and B cells, and of T cell to B cell costimulation in the regulation of bone turnover in young, adult and aged mice, and to evaluate the impact of pharmacological B cell depletion, and of T cell to B cell costimulation inhibitors, on B cell and/or total OPG production, bone turnover, and indices of bone structure in mice in vivo. In Specific Aim 1 we will investigate the impact of B cell depletion in mice in vivo using an anti-CD20 antibody that mimics the agent Rituximab, now used in humans to treat refractory Rheumatoid Arthritis and certain B cell lymphomas. In Specific Aim 2 we will investigate the role of costimulation in B cell OPG production; the specific T cell subsets involved; and how pharmacological suppression of T cell to B cell costimulation in mice alters B cell OPG production and bone turnover, using in vivo gain and loss of function models. These Specific Aims will: 1) provide critical data to validate our hypothesis that B cells control basal bone homeostasis in vivo through production of OPG, and regulated by costimulatory signals from T cells, in young, adult and aged mice; and 2) provide important information about the potential for skeletal side-effects relating to the clinical use of immunomodulatory pharmaceuticals to ameliorate disease. PUBLIC HEALTH RELEVANCE: Osteoporosis is endemic among Western societies. Fractures are already a serious medical problem among aging Veterans and in the general population and 1 in 2 females and 1 in 5 males over the age of 50 will suffer a bone fracture in their remaining lifetimes. Fractures lead to huge healthcare expenditures, loss of mobility, and morbidity. Hip fractures almost always require surgery and mortality rates are extremely high in aged individuals following surgery. Elucidating the mechanisms that regulate basal bone turnover in young and aged individuals is central to our understanding of the pathophysiology of bone diseases and to the design of new effective countermeasures. Furthermore, cancers, Rheumatoid Arthritis (RA) and other autoimmune diseases are prevalent in the aging VA population. Rituximab, a B cell depleting antibody, used to treat B cell Non-Hodgkin's lymphoma and CTLA4-Ig (Abatacept) a costimulation inhibitor, are rapidly becoming the standard of care for refractory RA, with new applications for these drugs under intensive investigation for amelioration of numerous conditions including Crohn's disease, psoriasis and psoriatic arthritis, systemic lupus erythematosus; multiple sclerosis; Type I Diabetes, and as anti-rejection agents following solid organ and bone marrow transplantation. Our preliminary studies suggest that these immune modifying agents may illicit a serious skeletal complication that may seriously impact Veteran health by inducing osteoporosis and increasing fracture risk. Understanding the potential complications associated with Rituximab and Abatacept therapy may allow for the modification of the therapeutic regime in order to monitor or address skeletal complications in patients undergoing long term therapy with immune-modulating agents.

描述（由申请人提供）： 骨质疏松症导致的骨折导致老年人的显著健康成本、发病率、活动能力丧失以及通常的死亡率。驱动骨质疏松症的骨破坏由破骨细胞（OC）介导，破骨细胞是在关键的破骨细胞生成细胞因子NF-：B受体激活剂（RANKL）的影响下形成的骨吸收细胞。RANKL活性受其生理性诱饵受体骨保护素（OPG）调节。从历史上看，OPG的产生一直与成骨细胞系细胞有关。然而，最近我们发现，在小鼠中，B细胞是体内OPG的重要补充来源，并且B细胞OPG的产生受到来自T细胞的共刺激信号如CD 40配体（CD 40 L）的调节。此外，面对成骨细胞OPG产量下降，老年小鼠中B细胞OPG产量显著上调。我们假设“淋巴细胞通过B细胞OPG的产生，并受T细胞共刺激的调节，是年轻小鼠基础骨稳态的关键调节因子，并部分缓解与衰老相关的骨吸收增强”。 调节免疫功能的新型治疗剂正处于紧张的研究中，用于治疗许多自身免疫性和炎性疾病，以及作为骨髓和实体器官移植中的抗排斥剂。这些药物对骨骼的长期影响尚不清楚，然而，我们的初步研究表明，免疫调节治疗的一个不可预见的后果可能是通过干扰B细胞OPG的产生来促进骨质疏松症。为了认可和扩展我们的初步发现并探索其潜在的临床意义，我们建议表征T细胞和B细胞以及T细胞与B细胞共刺激在年轻、成年和老年小鼠骨转换调节中的作用，并评估药理学B细胞耗竭以及T细胞与B细胞共刺激抑制剂对B细胞和/或总OPG产生的影响，骨转换和小鼠体内骨结构指数。在具体目标1中，我们将研究使用模拟利妥昔单抗的抗CD 20抗体在小鼠体内消除B细胞的影响，利妥昔单抗目前用于治疗人类难治性风湿性关节炎和某些B细胞淋巴瘤。在特定目标2中，我们将研究共刺激在B细胞OPG产生中的作用;涉及的特定T细胞亚群;以及使用体内功能获得和丧失模型，药理学抑制小鼠T细胞对B细胞共刺激如何改变B细胞OPG产生和骨转换。 这些具体目标将：1）提供关键数据以验证我们的假设，即B细胞通过产生OPG控制体内基础骨稳态，并受来自T细胞的共刺激信号调节，在年轻、成年和老年小鼠中;和2）提供关于与临床使用免疫调节药物改善疾病相关的骨骼副作用潜力的重要信息。 公共卫生相关性： 骨质疏松症是西方社会的地方病。骨折已经是老年退伍军人和普通人群中的一个严重的医疗问题，50岁以上的女性中有1/2和男性中有1/5将在其余生中遭受骨折。骨折导致巨大的医疗保健支出，丧失流动性和发病率。髋部骨折几乎总是需要手术，手术后老年人的死亡率极高。阐明调节年轻人和老年人基础骨转换的机制是我们理解骨疾病病理生理学和设计新的有效对策的核心。 此外，癌症，风湿性关节炎（RA）和其他自身免疫性疾病在老年VA人群中普遍存在。利妥昔单抗，一种B细胞耗竭抗体，用于治疗B细胞非霍奇金淋巴瘤和CTLA 4-IG（阿巴西普），共刺激抑制剂，正迅速成为难治性RA的护理标准，这些药物的新应用正在深入研究中，用于改善许多病症，包括克罗恩病、银屑病和银屑病关节炎、系统性红斑狼疮、多发性硬化症; I型糖尿病，以及作为实体器官和骨髓移植后的抗排斥药物。我们的初步研究表明，这些免疫调节剂可能会导致严重的骨骼并发症，可能会严重影响退伍军人的健康，诱导骨质疏松症和增加骨折的风险。了解与利妥昔单抗和阿巴西普治疗相关的潜在并发症可能允许修改治疗方案，以监测或解决接受免疫调节剂长期治疗的患者的骨骼并发症。