Immune Regulation of Bone Homeostasis

描述(由申请人提供)： 骨质疏松症引起的骨折会给老年人带来巨大的医疗成本、发病率、行动不便，甚至死亡。导致骨质疏松的骨质破坏是由破骨细胞(OCs)介导的，破骨细胞是在关键的破骨细胞因子受体-核因子激活因子(RANKL)影响下形成的骨吸收细胞。RANKL的活性受其生理诱饵受体护骨素(OPG)的调节。从历史上看，OPG的产生一直与成骨细胞系细胞有关。然而，我们最近发现，在小鼠体内，B细胞是OPG的重要补充来源，B细胞OPG的产生受到共刺激信号的调节，如T细胞来源的CD40配体(CD40L)。此外，在成骨细胞OPG产生下降的情况下，B细胞OPG的产生在老年小鼠中显著上调。我们假设“淋巴细胞，通过B细胞OPG的产生，并受T细胞共刺激调节，是幼鼠基础骨稳态的关键调节因素，并在一定程度上缓解了与衰老相关的骨吸收增强”。调节免疫功能的新型治疗药物正在被广泛研究，用于治疗多种自身免疫性和炎症性疾病，以及作为骨髓和实体器官移植的抗排斥药物。然而，这些药物对骨骼的长期影响尚不清楚，但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。为了证实和推广我们的初步发现，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细胞和B细胞的共刺激作用在调节幼年、成年和老年小鼠骨转换中的作用，并评估药理性B细胞耗竭和T细胞对B细胞和/或总OPG的产生、骨转换以及体内骨结构指数的影响。在具体目标1中，我们将在体内使用一种抗CD20抗体来研究B细胞枯竭对小鼠的影响，该抗体模仿药物Rituximab，目前用于人类治疗难治性类风湿性关节炎和某些B细胞淋巴瘤。在具体目标2中，我们将使用体内获得和丧失功能模型，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；以及药物抑制小鼠T细胞对B细胞的共刺激如何改变B细胞OPG的产生和骨转换。这些特定的目标将：1)提供关键数据来验证我们的假设，即B细胞通过在幼年、成年和老年小鼠体内通过产生OPG并受T细胞的共刺激信号调节来控制基础骨稳态；以及2)提供与临床使用免疫调节药物改善疾病相关的潜在骨骼副作用的重要信息。 公共卫生相关性： 骨质疏松症是西方社会的地方病。骨折在老年退伍军人和普通人群中已经是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。骨折会导致巨大的医疗费用、行动不便和发病率。髋部骨折几乎总是需要手术，而老年人手术后的死亡率极高。阐明年轻人和老年人基底骨转换的调节机制，对于我们理解骨疾病的病理生理学和设计新的有效的对策是至关重要的。此外，癌症、类风湿性关节炎(RA)和其他自身免疫性疾病在老年退伍军人中很常见。用于治疗B细胞非霍奇金淋巴瘤的B细胞耗竭抗体利妥昔单抗和共刺激抑制剂CTLA4-Ig(Abatacept)正迅速成为难治性RA的标准治疗药物，这些药物的新用途正在密切研究中，以改善包括克罗恩病、银屑病和银屑病关节炎、系统性红斑狼疮、多发性硬化症、I型糖尿病以及固体器官和骨髓移植后的抗排斥反应在内的多种疾病。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，导致骨质疏松症和增加骨折风险，从而严重影响退伍军人的健康。了解与Rituximab和abatacept治疗相关的潜在并发症可能允许修改治疗方案，以便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。

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.