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：
7990032
负责人：
Yin Tintut
金额：
$ 10万
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：
2009
资助国家：
美国
起止时间：
2009-12-07 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990032
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 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 Hormone Receptors Parathyroid Hormones 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 Transgenic Organisms Treatment Efficacy United States Universities attenuation base bone bone metabolism bone morphogenetic protein 2 bone turnover chemokine cytokine hormone resistance hormone sensitivity hormone therapy human PTH protein 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 public health relevance receptor receptor expression response trafficking

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Relevance to Public Health High cholesterol is common in patients with the low bone density disease, osteoporosis. Parathyroid hormone treatment is a promising therapy for osteoporosis, but evidence suggests that it may be much less effective in patients with high cholesterol. The proposed studies will determine how unmanaged cholesterol level reduces efficacy of the treatment so that corrective strategies can be developed.

描述（由申请人提供）：甲状旁腺激素（PTH）是骨代谢的关键调节剂，被用作合成代谢药物治疗骨质疏松症。最近的证据表明，脂质可能会影响骨代谢，并且在存在高脂血症的情况下，间歇性PTH疗法可能失败。这在临床上很重要，因为骨质疏松症的患者甚至在年龄上都普遍存在高脂血症。在高脂症状中，在组织的下皮空间中产生了低密度脂蛋白（LDL）的生物活性衍生物，从而触发了慢性炎症反应，包括氧化剂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表明，与WT小鼠相比，高脂小鼠的骨密度降低。我们的初步研究，无论是体外还是体内，现在都表明脂质抑制了PTH诱导的早期基因，包括Nurr1，包括成骨细胞基因的转录调节剂Nurr1，通过衰减环状AMP的产生和高脂型PTH诱导的Osteoanaanabolism in Vivo in Vivo in Vivo，通过衰减环状AMP的产生。在皮质骨中。这些发现强烈表明高脂血症会诱导PTH耐药性。 PTH耐药性是否处于分子和/或组织水平尚待确定。由于尽管有治疗，但骨质疏松症和高脂血症仍然普遍存在，因此了解脂质对基底（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方法。我们假设高脂血症增加的炎性脂蛋白减少了PTH合成代谢作用。基于我们的初步研究，在特定的目标1中，我们将在体外测试脂质对PTH诱导的环状AMP产生的抑制性机制是否在PTH受体表达，受体运输，下游在G蛋白激活水平下的水平。，或在腺苷酸环化酶激活水平上进一步下游。在特定的目标2中，我们将确定脂质诱导的PTH耐药性在体内发生的水平：在骨髓祖细胞的分化水平下，朝着成骨与成脂谱系的水平；成熟成骨细胞/骨细胞的合成代谢反应；和/或通过成骨细胞对破骨细胞生成因子的瞬时表达。我们将生成表达针对成骨细胞和骨细胞的绿色荧光蛋白的LDLR - / - 小鼠。在特定目标3中，我们将测试通过测量骨密度，组织态度学参数和高脂症（LDLR - / - ）小鼠的骨密度，组织形态学参数和骨转换标志物来减少高脂血症或抑制脂质氧化会反向PTH抗性。或过表达抗氧化酶，副氧酮酶-1。这些提出的研究将提供有关炎症性脂质如何抑制PTH诱导的骨代谢的洞察力，查明PTH信号传导途径中抑制作用的部位，并展示了反向脂质诱导的PTH失调的方法。公共卫生相关性：与公共卫生高胆固醇相关性，在低骨密度疾病，骨质疏松症患者中很常见。甲状旁腺激素治疗是骨质疏松症的一种有希望的疗法，但有证据表明，它在高胆固醇患者中可能有效得多。拟议的研究将决定不受管理的胆固醇水平如何降低治疗的疗效，从而可以制定纠正策略。