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）：脂肪细胞衍生的激素瘦素作用于包括骨骼在内的多个器官。瘦素对骨代谢的特定作用是有争议的，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。拟议的研究旨在检验新的假设，即瘦素在代谢骨疾病的病因学中扮演先前未知但重要的作用。瘦素充当能量储量足以支持骨骼生长和周转的宽敞允许因子信号传导大脑和骨细胞。然而，瘦素还可以作为促炎细胞因子起作用，并可以调节先天和适应性免疫反应。基于广泛的初步数据，假设瘦素通过加剧致病性促炎性免疫反应，是扩大炎症驱动骨骼损失的重要合并症。提出的瘦素调节的途径靶向成骨细胞，免疫细胞和下丘脑。具体而言，高稀释血症会导致促炎反应的升高，从而通过扩增由共存炎症引起的有害骨骼作用，从而导致骨骼的其他附带损害。潜在的炎症可能是由于多种因素，包括感染，牙周疾病，哮喘，雌激素缺乏，关节炎或骨科植入物碎片。初步研究表明，缺乏瘦素的OB/OB小鼠对聚乙烯颗粒诱导的骨质流失具有高度抗性（放置在钙含量上，以模拟关节置换术磨损颗粒诱导的骨溶解）强烈支持这一假设。我们建议通过实现两个目标来检验我们的假设。 AIM 1：定义高勒普汀血症对炎症驱动骨质流失的贡献。在WT和缺乏瘦素的OB/OB小鼠中，将诱发局部炎症，其中瘦素受体占用率将被实验操纵。将测量炎症，局部和全身骨质流失以及脾脏中免疫细胞的激活。 AIM 2：确定外周与下丘脑瘦素信号传导在炎症驱动的骨质流失中的作用。研究旨在评估瘦素通过在免疫细胞上激活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传导，以及这些调节途径是否会融合到炎症驱动驱动的骨损失。为了克服与手术相关的炎症的混杂作用，长时间下丘脑瘦素基因治疗将用于选择性地恢复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，将在瘦素受体缺陷型DB/DB小鼠中选择性地恢复周围瘦素信号传导。成功完成拟议的研究将对骨气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，确定瘦素调节的周围和中心途径的精确作用是预期的，以防止/治疗炎症驱动的骨质流失。 公共卫生相关性：瘦素是一种对多个器官（包括免疫系统和骨骼）的激素。拟议的研究旨在检验新的假设，即通过充当免疫系统调节剂，瘦素是炎症引起的骨质流失的关键因素。这种知识很重要，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。