REGULATION OF PTH-INDUCED BONE ANABOLISM BY INFLAMMATORY LIPIDS

炎性脂质对 PTH 诱导的骨合成代谢的调节

• 批准号: 7130286
• 负责人: Yin Tintut
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-17 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130286
• 关键词: biological signal transduction; bone density; bone metabolism; cAMP response element binding protein; cell differentiation; comorbidity; genetically modified animals; hyperlipidemia; inflammation; laboratory mouse; low density lipoprotein; nerve growth factors; osteoblasts; osteoclasts; osteoporosis; parathyroid hormones; physiologic bone resorption; protein kinase A; regulatory gene; skeletal disorder chemotherapy; skeletal pharmacology

DESCRIPTION (provided by applicant): Intermittent PTH injection is a promising treatment for osteoporosis, which afflicts millions. Recent evidence suggests that this treatment strategy may fail in patients with hyperlipidemia. Osteoporosis has been associated with hyperlipidemia in an age-independent manner. In the hyperlipidemic condition, bioactive derivatives of low-density lipoproteins (LDL) are generated in the subendothelial space of tissues, triggering inflammatory processes such as atherosclerosis. We have found that these inflammatory lipoproteins are also present in bone, and they inhibit osteoblastic differentiation. In additional studies, we found that hyperlipidemic mice have reduced bone density compared to normolipemic mice. Our preliminary studies, both in vitro and in vivo, now show that inflammatory lipoproteins also inhibit PTH-induced primary response genes, including Nurrl, a transcriptional regulator of osteoblastic genes, strongly suggesting that hyperlipidemia may also interfere with anabolic effects of PTH. Since hyperlipidemia remains widespread despite treatment, understanding its effects on bone metabolism may be crucial for devising effective PTH treatments. In this exploratory proposal, we hypothesize that hyperlipidemia, through inflammatory lipoproteins, reduces PTH anabolic effects. Based on our preliminary studies, in Specific Aim 1. we will test whether the mechanism of lipid inhibition of Nurrl expression is at the level of PKA activation or downstream at the level of promoter stimulation by transcription factor cAMP-response element binding protein (CREB), and its coactivator, CREB binding protein (CBP/p300). In Specific Aim 2. we will test whether hyperlipidemia reduces PTH-induced bone anabolism in vivo using intermittent PTH injection in normolipemic control (C57BL/6) and genetically hyperlipidemic Idlr(-/-) and apoE(-/-) mice. These proposed studies are expected to reveal how inflammatory lipids affect PTH-induced anabolism and the site of inhibitory activity within the intracellular signaling pathway. If successful, the findings will set the stage for a future R01 application to identify therapeutic strategies that rescue PTH efficacy in the face of hyperlipidemia. Such knowledge may significantly impact pharmacological interventions for osteoporosis. Lay Summary. High cholesterol is common in patients with the low bone density disease, osteoporosis. Recent studies suggest that the promising new therapy for osteoporosis, intermittent parathyroid hormone injection, may be significantly less effective in those with high cholesterol. The proposed studies will determine how high cholesterol reduces efficacy of parathyroid hormone so that corrective strategies can be developed.

描述（由申请人提供）：间歇性 PTH 注射是治疗骨质疏松症的一种有前景的方法，骨质疏松症困扰着数百万人。最近的证据表明，这种治疗策略对于高脂血症患者可能会失败。骨质疏松症与高脂血症以与年龄无关的方式相关。在高脂血症情况下，组织内皮下间隙会产生低密度脂蛋白（LDL）的生物活性衍生物，引发动脉粥样硬化等炎症过程。我们发现这些炎性脂蛋白也存在于骨骼中，它们抑制成骨细胞的分化。在其他研究中，我们发现与正常血脂小鼠相比，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，炎症脂蛋白也会抑制 PTH 诱导的初级反应基因，包括成骨细胞基因的转录调节因子 Nurrl，强烈表明高脂血症也可能干扰 PTH 的合成代谢作用。由于尽管进行了治疗，高脂血症仍然普遍存在，因此了解其对骨代谢的影响对于设计有效的 PTH 治疗方法可能至关重要。 在这个探索性提议中，我们假设高脂血症通过炎性脂蛋白降低 PTH 合成代谢作用。基于我们的初步研究，在具体目标1中，我们将测试Nurrl表达的脂质抑制机制是在PKA激活水平还是下游转录因子cAMP反应元件结合蛋白（CREB）刺激的启动子水平，及其共激活剂 CREB ​​结合蛋白 (CBP/p300)。在具体目标 2 中，我们将在血脂正常对照 (C57BL/6) 和遗传性高脂血症 Idlr(-/-) 和 apoE(-/-) 小鼠中间歇性注射 PTH，测试高脂血症是否会减少 PTH 诱导的体内骨合成代谢。这些拟议的研究有望揭示炎症脂质如何影响 PTH 诱导的合成代谢以及细胞内信号通路内的抑制活性位点。如果成功，这些发现将为未来 R01 的应用奠定基础，以确定在高脂血症时挽救 PTH 疗效的治疗策略。这些知识可能会显着影响骨质疏松症的药物干预。 平铺总结。高胆固醇在患有低骨密度疾病、骨质疏松症的患者中很常见。最近的研究表明，间歇性甲状旁腺激素注射这一有前景的骨质疏松症新疗法对于高胆固醇患者的疗效可能明显较差。拟议的研究将确定高胆固醇如何降低甲状旁腺激素的功效，以便制定纠正策略。