The Role of Leptin in Inflammation-Driven Bone Loss

瘦素在炎症驱动的骨质流失中的作用

• 批准号: 10212084
• 负责人: URSZULA T IWANIEC
• 金额: $ 39.1万
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212084
• 关键词: Adoptive Transfer; Adult; Aging; B-Lymphocytes; Bone Growth; Calvaria; Cell Lineage; Cell Proliferation; Cell membrane; Cells; Chronic; Complex; Coupling; Data; Disease; Elderly; Elements; Energy Intake; Energy Metabolism; Engraftment; Equilibrium; Failure; Female; Fracture; Goals; Growth; Health; Hematopoietic; Hematopoietic stem cells; Homeostasis; Hormones; Immune; Immune signaling; Immune system; Immunoglobulin M; Inflammation; Inflammatory; Interruption; Knowledge; Leptin; Lymphoid Cell; Maintenance; Mediating; Modeling; Molecular; Mus; Myeloid Cells; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Neuraxis; Organ; Osteoblasts; Osteoclasts; Osteolysis; Pathologic; Pathology; Peripheral; Physiological; Play; Polyethylenes; Proto-Oncogene Protein c-kit; Regulation; Regulatory Element; Research; Role; Signal Transduction; Skeleton; Strategic Planning; T-Cell Receptor; T-Lymphocyte; Testing; adipokines; base; bone; bone loss; bone mass; bone metabolism; bone quality; bone turnover; chemokine receptor; db/db mouse; energy balance; insight; leptin receptor; male; mast cell; monocyte; particle; prevent; reconstitution; recruit; skeletal; skeletal tissue; therapeutic target; therapy development; tool

PROJECT SUMMARY Leptin, originally identified as a regulator of energy metabolism, is required for normal bone growth and turnover, making the adipokine an attractive candidate for coupling optimal bone accrual and turnover balance to energy availability. However, not all skeletal actions of leptin are beneficial; there is compelling evidence that leptin contributes to aging-related skeletal pathologies by promoting a proinflammatory cascade mediating inflammation-driven bone loss. The molecular mechanisms mediating the skeletal actions are poorly defined. We have strong preliminary data indicating that leptin influences bone metabolism, both beneficially and detrimentally, by activating leptin receptor (OB-R) on cells (predominately immune cells) derived from hematopoietic stem cells (HSCs). Based on this, we hypothesize that: (1) leptin signaling by immune cells is necessary for normal bone growth, maturation and turnover, but (2) in the presence of chronic inflammation, leptin signaling by immune cells promotes net bone loss. The proposed research will test these hypotheses in male and female mice by accomplishing two Specific Aims. Specific Aim 1: Determine the contribution of leptin signaling by immune cells to bone accrual and turnover balance. We will reconstitute the immune system of growing and adult male and female mice with HSCs from OB-R+ wild type (WT) or OB-R- db/db mice using adoptive transfer to establish the overall contribution of OB-R on immune cells to leptin regulation of bone accrual in growing mice and turnover balance in adult mice, respectively. We will then determine if the skeletal actions of leptin are primarily mediated via OB-R on cells in the osteoclast lineage by adoptively transferring OB-R+ and OB-R- monocytes into mice with reduced ability to form osteoclasts (Ccr2- mice). Specific Aim 2: Determine the contribution of leptin signaling by immune cells to inflammation-driven bone loss. We will reconstitute the immune system of growing and adult male and female mice with HSCs from OB-R+ or OB-R- mice as in Specific Aim 1 and induce local inflammation by placing polyethylene particles over calvaria to model aseptic periprosthetic bone loss. These studies will establish the overall contribution of OB-R on immune cells to inflammation-driven bone loss. The contribution of OB-R on immune cell subsets to normal bone turnover balance and particle-induced osteolysis in adult mice will then be evaluated following engraftment of subsets of OB-R+ and OB-R- immune cells into mice unable to generate/recruit monocytes (Ccr2-), T-cells (Tcra KO), B-cells (muMT-), or mast cells (KitW-sh). Successful completion of this research will have a major impact on the field by expanding existing concepts regarding the role of leptin in skeletal health and disease. Our approach will provide a powerful tool for unraveling mechanisms mediating the complex actions of leptin on the skeleton and immune systems. The proposed research has the potential to provide new insights for the development of interventions to interrupt leptin-mediated inflammatory cascades without compromising the beneficial skeletal actions of the adipokine.

项目摘要 瘦素最初被确定为能量代谢的调节剂，是正常骨生长和 营业额，使脂肪因子成为耦合最佳骨骼和离职的有吸引力的候选者 平衡能源可用性。但是，并非所有瘦素的骨骼作用都是有益的。有令人信服的 瘦素通过促进促炎性级联反应有助于瘦素有助于衰老相关的骨骼病理 介导炎症驱动的骨质流失。介导骨骼作用的分子机制是 定义不佳。我们有强大的初步数据，表明瘦素会影响骨代谢 通过在细胞上激活瘦素受体（OB-R）（主要是免疫细胞），有益地和有害 源自造血干细胞（HSC）。基于此，我们假设：（1）通过 免疫细胞对于正常的骨骼生长，成熟和周转是必要的，但是（2） 慢性炎症，免疫细胞的瘦素信号传导可促进净骨质流失。拟议的研究将 通过实现两个具体目标来检验男性和雌性小鼠中的这些假设。具体目标1： 确定免疫细胞对骨骼应计和周转平衡的瘦素信号传导的贡献。 我们将使用来自OB-R+的HSC来重建生长和成年男性和雌性小鼠的免疫系统 野生型（WT）或OB-R-dB/db小鼠使用过继转移来确定OB-R的整体贡献 免疫细胞对成年小鼠的生长小鼠的瘦蛋白调节骨骼应计的调节， 分别。然后，我们将确定瘦素的骨骼作用是否主要通过OB-R介导 在破骨细胞谱系中，通过降低的OB-R+和OB-R-单核细胞转移到小鼠中。 形成破骨细胞（CCR2-小鼠）的能力。特定目标2：确定瘦素信号传导的贡献 免疫细胞以炎症驱动的骨质流失。我们将重建生长的免疫系统和 与特定AIM 1一样 通过将聚乙烯颗粒放在钙钙上，以模拟无菌人修复的骨质流失来炎症。这些 研究将确定OB-R对免疫细胞对炎症驱动骨质流失的总体贡献。这 OB-R对免疫细胞亚群的贡献对正常的骨转换平衡和颗粒诱导的骨溶解的贡献 在成年小鼠中，将在植入OB-R+和OB-R-免疫细胞的亚群后评估 小鼠无法产生/募集单核细胞（CCR2-），T细胞（TCRA KO），B细胞（MUMT-）或肥大细胞（KITW-SH）。 成功完成这项研究将通过扩大现有概念对该领域产生重大影响 关于瘦素在骨骼健康和疾病中的作用。我们的方法将为 揭示介导瘦素对骨骼和免疫系统的复杂作用的机制。这 拟议的研究有可能为开发干预措施提供新的见解 瘦素介导的炎症级联反应，而不会损害脂肪因子的有益骨骼作用。