REGULATION OF PTH-INDUCED BONE ANABOLISM BY INFLAMMATORY LIPIDS

描述(申请人提供)：间歇性注射甲状旁腺素是一种很有前途的治疗骨质疏松症的方法，数百万人患有骨质疏松症。最近的证据表明，这种治疗策略可能在高脂血症患者中失败。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)的生物活性衍生物会在组织的内皮下间隙中产生，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。我们在体外和体内的初步研究表明，炎性脂蛋白也抑制甲状旁腺素诱导的初级反应基因，包括成骨基因的转录调节因子Nurr1，这强烈表明高脂血症也可能干扰甲状旁腺素的合成代谢作用。由于高脂血症在治疗后仍然普遍存在，了解其对骨代谢的影响对于设计有效的甲状旁腺激素治疗方法可能是至关重要的。 在这个探索性的提案中，我们假设高脂血症通过炎性脂蛋白减少了甲状旁腺素合成代谢的影响。在前期研究的基础上，有针对性地1.检测转录因子cAMP反应元件结合蛋白(CREB)及其共激活因子CREB结合蛋白(CBP/p300)对Nurr1基因表达的抑制机制是在PKA激活水平还是在启动子刺激的下游水平。2.在正常对照组(C57BL/6)和遗传性高脂血症Idlr(-/-)和apoE(-/-)小鼠中，采用间歇注射甲状旁腺素的方法，在体内检测高脂血症是否降低甲状旁腺素诱导的骨合成代谢。这些拟议的研究有望揭示炎性脂类如何影响甲状旁腺素诱导的合成代谢，以及细胞内信号通路中抑制活性的位置。如果成功，这些发现将为未来R01的应用奠定基础，以确定在面对高脂血症时挽救甲状旁腺素疗效的治疗策略。这些知识可能会对骨质疏松症的药物干预产生重大影响。 Laye摘要。高胆固醇常见于骨密度低的骨质疏松症患者。最近的研究表明，治疗骨质疏松症的有前景的新疗法--间歇性甲状旁腺激素注射，对高胆固醇者的疗效可能会显著降低。拟议的研究将确定高胆固醇如何降低甲状旁腺激素的疗效，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.