Adipsin from bone marrow fat as a regulator of bone remodeling

来自骨髓脂肪的脂肪素作为骨重塑的调节剂

• 批准号: 10064759
• 负责人: NICOLE AARON
• 金额: $ 4.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064759
• 关键词: Address; Adipocytes; Adipose tissue; Adverse effects; Affect; Age-Related Bone Loss; Alternative Complement Pathway; Antibodies; Arginine; Attenuated; Biological Assay; Bone Diseases; Bone Marrow; Bone remodeling; Cardiovascular Diseases; Cell Culture Techniques; Cells; Clinical; Complement 3; Complement Factor D; Deacetylation; Deterioration; Development; Endocrine; Environment; Equilibrium; Fatty acid glycerol esters; Fracture; Health; Heart; Hematopoietic; Homeostasis; Hormones; Impairment; Inflammation; Insulin Resistance; Knockout Mice; Laboratories; Lead; Lipids; Liver; Marrow; Mature Bone; Mediating; Mediator of activation protein; Mesenchymal Differentiation; Mesenchymal Stem Cells; Metabolic; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Organ; Osteoblasts; Osteogenesis; Osteoporosis; Outcome; Oxidative Stress; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Play; Post-Translational Protein Processing; Prevalence; Process; Proteins; Regulation; Research Design; Research Personnel; Risk; Role; Signal Transduction; Testing; Visceral; adipocyte biology; adipokines; bone; bone cell; bone health; bone loss; complement system; diabetes mellitus therapy; geographic atrophy; insulin sensitizing drugs; lipid biosynthesis; loss of function; mouse model; new therapeutic target; novel; osteogenic; protective effect; response; skeletal; stem cell differentiation; stem cells; transcription factor

PROJECT SUMMARY Current studies aim to understand the deleterious effects of adiposity on visceral organs such as the heart and liver. Less is understood about the effect of adipose tissue on the development and regulation of bone. Obesity is highly correlated with conditions of bone loss, including osteoporosis. Additionally, the loss of bone is associated with an increase in adiposity within the bone marrow niche. These bone marrow adipocytes (BMA) originate from the same progenitor cell as osteoblasts, the precursors to mature bone-forming cells. Activation of PPARg, an important transcription factor found primarily in adipocytes, drives adipogenesis at the expense of osteoblastogenesis. PPARg activation is also associated with reduced inflammation and the repartitioning of lipids away from organs ill-equipped to cope with a lipotoxic environment, making it a good target for insulin- sensitizing drugs known as Thiazolidines (TZD). Unfortunately, clinical use of TZDs is associated with increased risk for bone fractures due to impaired skeletal integrity. As such, maintaining skeletal health in obese patients, particularly those receiving TZD treatment, has become a critical challenge. Previously identified post-translational modifications (PTM) of PPARg have dissociated the insulin-sensitizing effects of TZD treatment from the negative outcomes. The constitutive deacetylation of Lys268 and Lys293 by conversion to Arginine residues in a mouse model has been shown to ameliorate bone loss and reduce marrow adiposity. To further elucidate the mechanism through which this PPARg PTM protects bone deterioration, the investigator proposes to uncover the functional role that bone marrow adipocytes play within the hematopoietic niche, including the extent to which BMA-derived adipokines contribute to skeletal remodeling. Specifically, she plans to identify adipsin as a key adipokine that is altered in response to PPARg deacetylation and is a potential modulator of the balance between marrow adipocytes and bone cells. In Aim 1 the investigator will identify adipsin as a mediator of the bone protective effect caused by PPARg deacetylation. Furthermore, she plans to elucidate the mechanism through which adipsin mediates the crosstalk between bone and bone marrow adipocytes in Aim 2 by assessing the role of adipsin released from peripheral and bone marrow adipose tissue using primary cells and an adipsin knockout mouse model. In addition to its potential role in bone regulation, adipsin is known to be involved in the alternative pathway of the complement system. In Aim 3 she plans to establish the role of the complement system in bone homeostasis through adipsin. Ultimately, this study will identify the molecular mechanism by which PPARg deacetylation selectively protects bone homeostasis. The identification of adipsin as a novel regulator of skeletal remodeling processes will advance the field of adipocyte biology by elucidating a novel adipokine to connect fat and bone.

项目摘要 目前的研究旨在了解肥胖对心脏等内脏器官的有害影响， 肝脏关于脂肪组织对骨骼发育和调节的影响了解较少。肥胖 与骨质流失，包括骨质疏松症的状况高度相关。此外，骨丢失是 与骨髓龛内肥胖增加相关。这些骨髓脂肪细胞（BMA） 与成骨细胞起源于相同的祖细胞，成骨细胞是成熟骨形成细胞的前体。激活 PPARg是一种主要在脂肪细胞中发现的重要转录因子，它以牺牲 成骨细胞生成PPARg活化也与炎症减少和细胞内蛋白质的再分配有关。 脂质远离器官，使其无法科普脂毒性环境，使其成为胰岛素的良好靶点- 致敏药物称为噻唑烷（TZD）。不幸的是，TZD的临床使用与增加的 由于骨骼完整性受损而导致骨折的风险。因此，维持肥胖患者的骨骼健康， 特别是那些接受TZD治疗的患者，已经成为一个严峻的挑战。 先前鉴定的PPARg的翻译后修饰（PTM）已经解离了胰岛素增敏的胰岛素受体。 TZD治疗的负面影响。Lys 268和Lys 293的组成型脱乙酰化， 在小鼠模型中转化为精氨酸残基已显示出改善骨丢失并减少骨髓 肥胖症为了进一步阐明PPARg PTM保护骨退化的机制， 研究人员提议揭示骨髓脂肪细胞在造血系统中发挥的功能作用 利基，包括在何种程度上，BM衍生的脂肪因子有助于骨骼重塑。她具体 计划将adipsin确定为一种关键的脂肪因子，它在PPARg去乙酰化反应中发生改变， 骨髓脂肪细胞和骨细胞之间平衡的调节剂。 在目标1中，研究者将确定脂蛋白酶作为由PPARg引起的骨保护作用的介质 去乙酰化此外，她计划阐明脂蛋白酶介导串扰的机制 Aim 2中骨和骨髓脂肪细胞之间的关系，通过评估外周血中释放的脂蛋白酶的作用， 和骨髓脂肪组织中的细胞和脂蛋白酶敲除小鼠模型。除了其 由于在骨调节中的潜在作用，已知脂蛋白酶参与补体的旁路途径 系统在目标3中，她计划通过脂蛋白酶确定补体系统在骨稳态中的作用。 最终，这项研究将确定PPARg去乙酰化选择性保护的分子机制。 骨稳态Adipsin作为一种新的骨骼重建过程调节剂的鉴定将 通过阐明连接脂肪和骨的新型脂肪因子，推进脂肪细胞生物学领域。