The Role of Leptin in Inflammation-driven Bone Loss

描述(申请人提供)：脂肪细胞衍生的激素瘦素作用于多个器官，包括骨骼。瘦素对骨代谢的具体作用存在争议，有证据表明瘦素具有直接的骨合成代谢作用和间接的下丘脑介导的分解代谢作用。这项拟议的研究旨在检验新的假设，即瘦素在代谢性骨骼疾病的病因学中发挥着以前未被认识但却很重要的作用。瘦素作为一种开/关允许因子，向大脑和骨骼细胞发出信号，表明能量储备足以支持骨骼的生长和周转。然而，瘦素也是一种促炎细胞因子，可以调节先天免疫反应和获得性免疫反应。基于大量的初步数据，假设瘦素通过加剧致病的促炎免疫反应，作为一个重要的共病因素，放大炎症引起的骨丢失。所提出的瘦素调节通路针对成骨细胞、免疫细胞和下丘脑。具体地说，高瘦素血症有助于提高促炎反应，通过放大共存炎症引起的有害骨骼影响，导致对骨骼的额外附带损害。潜在的炎症可能是由多种因素引起的，包括感染、牙周病、哮喘、雌激素缺乏、关节炎或骨科植入物碎片。初步研究表明，瘦素缺乏的ob/ob小鼠对聚乙烯颗粒(放置在颅骨上以模拟关节置换磨损颗粒诱导的骨溶解)引起的骨丢失具有高度的抵抗力，强烈支持这一假说。我们建议通过实现两个目标来检验我们的假设。目的1：明确高瘦素血症对炎症引起的骨丢失的影响。WT和瘦素缺乏的ob/ob小鼠将被诱导局部炎症，其中瘦素受体的水平将被实验性地操纵。将测量炎症程度、局部和全身骨丢失以及脾中免疫细胞的激活。目的2：确定外周瘦素和下丘脑瘦素信号在炎症引起的骨丢失中的各自作用。研究旨在评估瘦素通过激活免疫细胞上的瘦素受体直接调节免疫功能的程度和/或通过下丘脑继电器增加交感神经信号间接调节免疫功能的程度，以及这些调节途径是否会聚在一起加剧炎症引起的骨丢失。为了克服手术相关炎症的混杂效应，将使用长期的下丘脑瘦素基因治疗来选择性地恢复ob/ob小鼠下丘脑中的瘦素信号。通过移植WT造血干细胞，瘦素受体缺陷db/db小鼠的外周瘦素信号将选择性地恢复到免疫细胞。这项拟议研究的成功完成将对骨免疫学这一新兴领域产生重大影响，并有望从根本上改变我们对瘦素的生理和病理作用的理解。最后，确定瘦素调节的外周和中央通路的确切作用有望确定预防/治疗炎症引起的骨丢失的靶点。

DESCRIPTION (provided by applicant): The adipocyte-derived hormone leptin acts on multiple organs, including bone. The specific effects of leptin on bone metabolism are controversial, with evidence for direct bone anabolic actions and indirect hypothalamic- mediated catabolic actions. The proposed research is designed to test the novel hypothesis that leptin plays a previously unrecognized but important role in the etiology of metabolic bone disease. Leptin acts as an on/off permissive factor signaling brain and bone cells that energy reserves are adequate to support bone growth and turnover. However, leptin also functions as a proinflammatory cytokine and can modulate both innate and adaptive immune responses. Based on extensive preliminary data, it is hypothesized that leptin, by exacerbating pathogenic proinflammatory immune responses, acts as an important comorbidity factor to amplify inflammation-driven bone loss. The proposed leptin-regulated pathways target osteoblasts, immune cells, and the hypothalamus. Specifically, hyperleptinemia contributes to elevated proinflammatory responses, resulting in additional collateral damage to bone by amplifying the detrimental skeletal effects caused by coexisting inflammation. The underlying inflammation can be due to a variety of factors, including infection, periodontal disease, asthma, estrogen deficiency, arthritis, or orthopedic implant debris. Preliminary studies showing that leptin-deficient ob/ob mice are highly resistant to bone loss induced by polyethylene particles (placed onto calvarium to model arthroplasty wear particle-induced osteolysis) strongly support this hypothesis. We propose to test our hypothesis by accomplishing two Aims. Aim 1: Define the contribution of hyperleptinemia to inflammation-driven bone loss. Local inflammation will be induced in WT and leptin-deficient ob/ob mice in which levels of leptin receptor occupancy will be experimentally manipulated. Magnitude of inflammation, local and systemic bone loss, and activation of immune cells in the spleen will be measured. Aim 2: Determine the respective roles of peripheral versus hypothalamic leptin signaling in inflammation-driven bone loss. Studies are designed to evaluate the extent to which leptin modulates immune function directly via activation of leptin receptors on immune cells and/or indirectly by increasing sympathetic signaling through a hypothalamic relay, and if these regulatory pathways converge to exacerbate inflammation-driven bone loss. To overcome the confounding effects of surgery-associated inflammation, long duration hypothalamic leptin gene therapy will be used to selectively restore leptin signaling in the hypothalamus of ob/ob mice. Peripheral leptin signaling will be selectively restored to immune cells in leptin receptor-deficient db/db mice by transplantation of WT hematopoietic stem cells. Successful completion of the proposed research will have a major impact on the emerging field of osteoimmunology, and is expected to radically alter our understanding of the physiological and pathological actions of leptin. Finally, determining the precise role of leptin-modulated peripheral and central pathways is expected identify targets to prevent/treat inflammation-driven bone loss.