REGULATION OF PTH-INDUCED BONE ANABOLISM BY INFLAMMATORY LIPIDS

描述（由申请人提供）：间歇性甲状旁腺素注射是一种有前途的骨质疏松症治疗方法，数百万人深受其害。最近的证据表明，这种治疗策略可能会失败的高脂血症患者。骨质疏松症与高脂血症的关系与年龄无关。在高脂血症条件下，低密度脂蛋白（LDL）的生物活性衍生物在组织的内皮下空间中产生，引发炎症过程，如动脉粥样硬化。我们发现这些炎性脂蛋白也存在于骨中，它们抑制成骨细胞分化。在另外的研究中，我们发现高脂血症小鼠与正常脂血症小鼠相比骨密度降低。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PTH诱导的主要反应基因，包括Nurrl，成骨细胞基因的转录调节因子，强烈表明，高脂血症也可能干扰合成代谢的PTH的影响。由于高脂血症仍然普遍存在，尽管治疗，了解其对骨代谢的影响可能是至关重要的设计有效的PTH治疗。 在这个探索性的建议中，我们假设高脂血症，通过炎性脂蛋白，减少PTH合成代谢的影响。根据我们的初步研究，在具体目标1。我们将测试Nurr 1表达的脂质抑制机制是在PKA激活水平还是在转录因子cAMP-反应元件结合蛋白（CREB）及其共激活因子CREB结合蛋白（CBP/p300）的启动子刺激水平的下游。具体目标2。我们将在正常脂血对照（C57 BL/6）和遗传性高脂血症Idlr（-/-）和apoE（-/-）小鼠中使用间歇性PTH注射来测试高脂血症是否减少PTH诱导的体内骨抑制。这些拟议的研究有望揭示炎症脂质如何影响PTH诱导的抗凋亡和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R 01的应用奠定基础，以确定在高脂血症中挽救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。 Lay摘要。高胆固醇是常见的低骨密度疾病，骨质疏松症患者。最近的研究表明，骨质疏松症的有前途的新疗法，间歇性甲状旁腺激素注射，可能是显着降低高胆固醇的有效性。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。

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.