The Role of Leptin in Inflammation-driven Bone Loss

瘦素在炎症引起的骨质流失中的作用

• 批准号: 8239408
• 负责人: URSZULA T IWANIEC
• 金额: $ 32.9万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239408
• 关键词: Adipocytes; Arthritis; Arthroplasty; Asthma; Bone Growth; Bone Resorption; Calvaria; Cells; Chronic; Comorbidity; Complex; Data; Dose; Elderly; Estrogens; Etiology; Fracture; Hematopoietic stem cells; Hormones; Hypothalamic structure; Immune; Immune Cell Activation; Immune response; Immune system; Implant; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Leptin; Measures; Mediating; Mediator of activation protein; Metabolic Bone Diseases; Modeling; Operative Surgical Procedures; Organ; Orthopedics; Osteoblasts; Osteogenesis; Osteolysis; Pathway interactions; Periodontal Diseases; Peripheral; Physiological; Play; Polyethylenes; Postmenopausal Osteoporosis; Production; Regulatory Pathway; Research; Research Design; Resistance; Role; Senile Osteoporosis; Serum; Signal Transduction; Skeleton; Solid; Spleen; TNF gene; Testing; Transplantation; base; body system; bone; bone cell; bone loss; bone metabolism; bone turnover; brain cell; cost; cytokine; db/db mouse; defined contribution; design; gene therapy; immune function; innovation; leptin receptor; novel; particle; prevent; response; skeletal; tool

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. PUBLIC HEALTH RELEVANCE: Leptin is a hormone that acts on multiple organs, including the immune system and bone. The proposed research has been designed to test the novel hypothesis that leptin, by acting as an immune system modulator, is a key contributing factor to bone loss caused by inflammation. This knowledge is important because chronic inflammation results in bone loss, a common cause of bone fractures in the elderly.

描述（由申请人提供）：脂肪细胞来源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是有争议的，有直接骨合成代谢作用和间接下丘脑介导的分解代谢作用的证据。这项研究旨在验证瘦素在代谢性骨病病因学中发挥着以前未被认识但重要作用的新假设。瘦素作为一个开/关的许可因子信号脑和骨细胞的能量储备足以支持骨的生长和周转。然而，瘦素也作为促炎细胞因子发挥作用，并且可以调节先天性和适应性免疫应答。基于广泛的初步数据，假设瘦素通过加剧致病性促炎免疫反应，作为一个重要的共病因子放大炎症驱动的骨丢失。所提出的瘦素调节途径靶向成骨细胞、免疫细胞和下丘脑。具体而言，高瘦素血症有助于升高的促炎反应，通过放大由共存炎症引起的有害骨骼效应而导致对骨的额外附带损伤。潜在的炎症可能是由于多种因素，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，瘦素缺陷型ob/ob小鼠对聚乙烯颗粒（放置在颅骨上模拟关节成形术磨损颗粒诱导的骨质溶解）诱导的骨丢失具有高度抵抗力，这强烈支持了这一假设。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丢失的贡献。将在WT和瘦素缺陷型ob/ob小鼠中诱导局部炎症，其中瘦素受体占用水平将通过实验操作。将测量炎症程度、局部和全身骨丢失以及脾脏中免疫细胞的活化。目的2：确定外周和下丘脑瘦素信号在炎症驱动的骨丢失中各自的作用。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和/或通过下丘脑中继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加剧炎症驱动的骨丢失。为了克服手术相关炎症的混杂效应，将使用长持续时间的下丘脑瘦素基因治疗来选择性地恢复ob/ob小鼠下丘脑中的瘦素信号传导。通过移植WT造血干细胞，外周瘦素信号传导将选择性地恢复至瘦素受体缺陷db/db小鼠中的免疫细胞。这项研究的成功完成将对骨免疫学的新兴领域产生重大影响，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确切作用有望确定预防/治疗炎症驱动的骨丢失的靶点。 公共卫生相关性：瘦素是一种激素，作用于多个器官，包括免疫系统和骨骼。这项研究旨在验证一个新的假设，即瘦素作为一种免疫系统调节剂，是炎症引起的骨质流失的关键因素。这一知识很重要，因为慢性炎症会导致骨质流失，这是老年人骨折的常见原因。