The Role of Leptin in Inflammation-driven Bone Loss

描述（由申请人提供）：脂肪细胞衍生的激素瘦素作用于包括骨在内的多个器官。瘦素对骨代谢的具体影响是有争议的，有证据表明它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。拟议的研究旨在验证瘦素在代谢性骨病的病因学中起着以前未被认识但重要的作用的新假设。瘦素作为一种开/关许可因子，向大脑和骨细胞发出信号，表明能量储备足以支持骨骼生长和更新。然而，瘦素也作为一种促炎细胞因子，可以调节先天和适应性免疫反应。基于广泛的初步数据，我们假设瘦素通过加剧致病性促炎免疫反应，作为一个重要的合并症因素，放大炎症驱动的骨质流失。提出的瘦素调控途径以成骨细胞、免疫细胞和下丘脑为目标。具体来说，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效应，导致额外的骨骼附带损伤。潜在的炎症可由多种因素引起，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（放置在颅骨上模拟关节置换磨损颗粒诱导的骨溶解）引起的骨质流失具有高度抵抗力，有力地支持了这一假设。我们建议通过实现两个目标来检验我们的假设。目的1：确定高瘦素血症对炎症驱动的骨质流失的贡献。局部炎症将在WT和瘦素缺乏的ob/ob小鼠中诱导，其中瘦素受体占用水平将被实验操纵。测量炎症程度，局部和全身骨质流失，以及脾脏免疫细胞的激活。目的2：确定外周和下丘脑瘦素信号在炎症驱动的骨质流失中的各自作用。研究旨在评估瘦素通过激活免疫细胞上的瘦素受体和/或通过下丘脑中继增加交感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驱动的骨质流失。为了克服手术相关炎症的混杂效应，将使用长时间的下丘脑瘦素基因治疗来选择性地恢复ob/ob小鼠下丘脑的瘦素信号。WT造血干细胞移植可选择性地恢复瘦素受体缺陷db/db小鼠免疫细胞中的外周瘦素信号。这项研究的成功完成将对新兴的骨免疫学领域产生重大影响，并有望从根本上改变我们对瘦素生理和病理作用的理解。最后，确定瘦素调节的外周和中枢通路的精确作用有望确定预防/治疗炎症驱动的骨质流失的目标。

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.