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; 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注射是骨质疏松症的有前途的治疗方法，遭受了数百万的折磨。最近的证据表明，高脂血症患者这种治疗策略可能失败。骨质疏松症已与年龄无关的方式与高脂血症有关。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，从而触发炎症过程，例如动脉粥样硬化。我们发现这些炎性脂蛋白也存在于骨骼中，并且它们抑制成骨细胞分化。在其他研究中，我们发现高脂小鼠与正常小鼠相比降低了骨密度。我们的初步研究在体外和体内，现在表明炎性脂蛋白也抑制了PTH诱导的主要反应基因，包括Nurrl，包括Nurrl，这是成骨细胞基因的转录调节剂，强烈表明高脂血症也可能会介入PTH的合成代谢作用。由于高脂血症仍在普遍存在，因此了解其对骨代谢的影响对于设计有效的PTH治疗可能至关重要。 在这项探索性建议中，我们假设通过炎性脂蛋白降低了高脂血症，从而降低了PTH合成代谢作用。基于我们的初步研究，在特定的目标1中。我们将测试NurRL表达的脂质抑制的机制是否处于PKA激活水平或下游在转录因子cAMP响应元件结合蛋白（CREB）及其共激活剂CREB结合蛋白（CBP/P300）的启动子刺激水平上。在特定的目标2中。我们将测试高脂血症是否在正质性控制中使用间歇性PTH注射（C57BL/6）以及遗传性高脂症IDLR（ - / - ）和APOE（ - - - ）小鼠是否会降低PTH诱导的体内骨变性。这些提出的研究预计将揭示炎症性脂质如何影响PTH诱导的合成代谢和细胞内信号传导途径内抑制活性的位点。如果成功，这些发现将为未来的R01应用奠定基础，以确定面对高脂血症的PTH功效的治疗策略。这种知识可能会显着影响骨质疏松症的药理干预措施。 摘要摘要。高胆固醇在低骨密度疾病，骨质疏松症的患者中很常见。最近的研究表明，在高胆固醇的患者中，新的骨质疏松症，间歇性甲状旁腺激素注射的新疗法可能明显降低。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，从而制定纠正策略。