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，是正常骨骼生长所必需的， 转换，使脂肪因子成为一个有吸引力的候选人耦合最佳的骨积累和转换 平衡能源供应。然而，并非瘦素的所有骨骼作用都是有益的; 瘦素通过促进促炎级联反应导致衰老相关骨骼病理的证据 介导炎症驱动的骨丢失。介导骨骼活动的分子机制是 定义不好。我们有强有力的初步数据表明，瘦素影响骨代谢， 通过激活细胞（主要是免疫细胞）上的瘦素受体（OB-R）， 来源于造血干细胞（HSC）。基于此，我们假设：（1）瘦素信号通过 免疫细胞是正常骨生长、成熟和周转所必需的，但（2）在存在 慢性炎症，免疫细胞的瘦素信号促进净骨丢失。拟议的研究将 通过完成两个特定目标，在雄性和雌性小鼠中测试这些假设。具体目标1： 确定免疫细胞对瘦素信号传导对骨生成和转换平衡的贡献。 我们将用来自OB-R+的HSC重建生长期和成年雄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对 免疫细胞对瘦素调节生长期小鼠的骨生成和成年小鼠的周转平衡， 分别然后我们将确定瘦素的骨骼作用是否主要是通过OB-R介导的 通过将OB-R+和OB-R-单核细胞过继转移到小鼠中， 形成破骨细胞的能力（Ccr 2-小鼠）。具体目标2：通过以下方式确定瘦素信号传导的贡献： 免疫细胞对炎症导致的骨质流失的反应。我们将重建生长的免疫系统， 成年雄性和雌性小鼠与来自OB-R+或OB-R-小鼠的HSC（如特异性Aim 1中所述）一起诱导局部 通过在颅骨上放置聚乙烯颗粒来模拟假体周围无菌性骨丢失。这些 研究将确定OB-R在免疫细胞上对炎症驱动的骨丢失的总体贡献。的 OB-R对免疫细胞亚群对正常骨转换平衡和颗粒诱导的骨质溶解的贡献 然后在将OB-R+和OB-R-免疫细胞的亚群植入到 不能产生/募集单核细胞（Ccr 2-）、T细胞（Tcra KO）、B细胞（muMT-）或肥大细胞（KitW-sh）的小鼠。 这项研究的成功完成将通过扩展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。我们的方法将提供一个强大的工具， 阐明瘦素对骨骼和免疫系统的复杂作用机制。的 拟议的研究有可能为干预措施的发展提供新的见解， 瘦素介导的炎症级联反应，而不损害脂肪因子的有益骨骼作用。