Regulation of PTH-induced Osteoanabolism by Inflammatory Lipids

炎症脂质对 PTH 诱导的骨合成代谢的调节

基本信息

批准号：
8531558
负责人：
Yin Tintut
金额：
$ 0.15万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-22 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531558
关键词：
Accounting Adenylate Cyclase Adult Affect Age Agonist Anabolic Agents Anabolism Antioxidants Apolipoprotein E Arteries Atherosclerosis Attenuated Blood Vessels Bone Density Bone Matrix Bone Mineral Contents C57BL/6 Mouse Cardiovascular Diseases Cell Count Cells Cholesterol Chronic Collagen Type I Connecticut Cyclic AMP Cyclic AMP-Dependent Protein Kinases Deposition Diet Differentiation Antigens Disease Enzymes Epidemiology Family Fatty acid glycerol esters Fibrinogen GTP-Binding Proteins Generations Genes Goals Green Fluorescent Proteins Health Hormones Hyperlipidemia Immediate-Early Genes In Vitro Inflammatory Inflammatory Response Injection of therapeutic agent Intervention Kidney Diseases Label Lipids Lipoproteins Literature Liver Low-Density Lipoproteins Marrow Measures Modification Molecular Mus Nerve Growth Factors Nuclear Orphan Receptor Osteoblasts Osteocytes Osteoporosis Paraoxonase 1 Parathyroid Hormone Receptor Parathyroid gland Pathway interactions Patients Pharmacotherapy Phospholipids Plasma Population Prevalence Prevention Production Public Health Rattus Reaction Reactive Oxygen Species Recombinants Regimen Regulation Regulator Genes Research Personnel Role Signal Pathway Signal Transduction Site Stem cells Teriparatide Testing Therapeutic Thick Tissues Transgenes Transgenic Mice Treatment Efficacy United States Universities attenuation base bone bone metabolism bone morphogenetic protein 2 bone turnover chemokine cytokine hormone resistance hormone sensitivity hormone therapy in vitro testing in vivo inhibitor/antagonist insight member mouse model novel novel strategies osteoblast differentiation osteogenic overexpression oxidant stress oxidation particle progenitor promoter protein activation receptor receptor expression response trafficking

项目摘要

Parathyroid hormone (PTH) is a key regulator of bone metabolism and is used as anabolic pharmacotherapy for treatment of osteoporosis. Recent evidence suggests that lipids may affect bone metabolism and that intermittent PTH therapy may fail in the presence of hyperlipidemia. This is clinically important because hyperlipidemia is prevalent in patients with osteoporosis even accounting for age. In the hyperlipidemic condition, bioactive derivatives of low-density lipoproteins (LDL) are generated in the subendothelial space of tissues, triggering chronic inflammatory responses including oxidant stress and expression of cytokines and chemokines. We have found that these inflammatory lipoproteins/lipids are also present in bone and that they inhibit osteoblastic differentiation. In additional studies, we and other investigators demonstrated that hyperlipidemic mice have reduced bone density compared to WT mice. Our preliminary studies, both in vitro and in vivo, now show that lipids inhibit PTH-induced immediate early genes, including Nurr1, a transcriptional regulator of osteoblastic genes, by attenuating cyclic AMP production and that hyperlipidemia blunts PTH-induced osteoanabolism in vivo, primarily in cortical bone. These findings strongly suggest that hyperlipidemia induces PTH resistance. Whether PTH resistance is at the molecular and/or tissue level remains to be determined. Since osteoporosis and hyperlipidemia remain widespread despite treatment, understanding effects of lipids on basal (endogenous) and intermittent (exogenous) PTH may provide new approaches to osteoporosis. We hypothesize that inflammatory lipoproteins, which are increased in hyperlipidemia, reduce PTH anabolic effects. Based on our preliminary studies, in Specific Aim 1, we will test in vitro whether the inhibitory mechanism of lipids on PTH-induced cyclic AMP production is at the level of PTH receptor expression, receptor trafficking, downstream at the level of G-protein activation, or further downstream at the level of adenylate cyclase activation. In Specific Aim 2, we will identify the level at which lipid-induced PTH resistance occurs in vivo: at the level of differentiation of marrow progenitors toward osteogenic vs. adipogenic lineages; anabolic responses of mature osteoblasts/osteocytes; and/or transient expression of osteoclastogenic factors by osteoblasts. We will generate Ldlr-/- mice that express green fluorescent protein targeted to osteoblasts and osteocytes. In Specific Aim 3, we will test whether reducing hyperlipidemia or inhibiting lipid oxidation will reverse PTH resistance in vivo by measuring bone density, histomorphometric parameters and bone turnover markers in the hyperlipidemic (Ldlr-/-) mice that are treated with liver X receptor agonists or that overexpress the anti-oxidant enzyme, paraoxonase-1. These proposed studies will provide insights into how inflammatory lipids inhibit PTH-induced osteoanabolism, pinpoint the site of inhibitory action within the PTH signaling pathway, and demonstrate approaches to reverse lipid-induced PTH dysregulation.

甲状旁腺激素（PTH）是骨代谢的关键调节剂，被用作治疗骨质疏松症的合成代谢药物。最近的证据表明，脂质可能会影响骨代谢，并且在高脂血症存在的情况下，间歇性 PTH 治疗可能会失败。这在临床上很重要，因为即使考虑到年龄，高脂血症在骨质疏松症患者中也很普遍。在高脂血症条件下，组织内皮下间隙中会产生低密度脂蛋白（LDL）的生物活性衍生物，引发慢性炎症反应，包括氧化应激以及细胞因子和趋化因子的表达。我们发现这些炎性脂蛋白/脂质也存在于骨骼中，并且它们抑制成骨细胞分化。在其他研究中，我们和其他研究人员证明，与野生型小鼠相比，高脂血症小鼠的骨密度降低。我们的体外和体内初步研究现在表明，脂质通过减弱环 AMP 的产生来抑制 PTH 诱导的立即早期基因，包括 Nurr1（成骨细胞基因的转录调节因子），并且高脂血症会减弱 PTH 诱导的体内骨合成代谢，主要是在皮质骨中。这些发现强烈表明高脂血症会诱发 PTH 抵抗。 PTH 耐药性是否存在于分子和/或组织水平仍有待确定。由于尽管进行了治疗，骨质疏松症和高脂血症仍然普遍存在，了解脂质对基础（内源性）和间歇性（外源性）PTH 的影响可能会为骨质疏松症提供新的治疗方法。我们假设高脂血症时炎症脂蛋白增加，会降低 PTH 合成代谢作用。基于我们的初步研究，在具体目标1中，我们将在体外测试脂质对PTH诱导的环AMP产生的抑制机制是否在PTH受体表达、受体运输水平、下游G蛋白激活水平，或更下游的腺苷酸环化酶激活水平。在具体目标 2 中，我们将确定体内脂质诱导的 PTH 抵抗发生的水平：骨髓祖细胞向成骨谱系与脂肪形成谱系的分化水平；成熟成骨细胞/骨细胞的合成代谢反应；和/或成骨细胞瞬时表达破骨细胞因子。我们将产生表达针对成骨细胞和骨细胞的绿色荧光蛋白的 Ldlr-/- 小鼠。在具体目标 3 中，我们将通过测量用肝 X 受体激动剂治疗的高脂血症 (Ldlr-/-) 小鼠的骨密度、组织形态学参数和骨转换标志物来测试降低高脂血症或抑制脂质氧化是否会逆转体内 PTH 抵抗或者过度表达抗氧化酶 paraoxonase-1。这些拟议的研究将深入了解炎症脂质如何抑制 PTH 诱导的骨合成代谢，查明 PTH 信号通路内的抑制作用位点，并展示逆转脂质诱导的 PTH 失调的方法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exosomes: nanosized cellular messages.

DOI：
10.1161/circresaha.115.306324
发表时间：
2015-04-10
期刊：
Circulation research
影响因子：
20.1
作者：
Tintut Y;Demer LL
通讯作者：
Demer LL

The effects of hyperlipidemia on implant osseointegration in the mouse femur.

DOI：
10.1563/aaid-joi-d-13-00105
发表时间：
2015-04
期刊：
The Journal of oral implantology
影响因子：
0
作者：
Keuroghlian A;Barroso AD;Kirikian G;Bezouglaia O;Tintut Y;Tetradis S;Moy P;Pirih F;Aghaloo T
通讯作者：
Aghaloo T

Protective Role of Smad6 in Inflammation-Induced Valvular Cell Calcification.