REGULATION OF PTH-INDUCED BONE ANABOLISM BY INFLAMMATORY LIPIDS

描述（由申请人提供）：间歇性注射甲状旁腺激素是一种很有前途的治疗骨质疏松症的方法，它折磨着数百万人。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）的生物活性衍生物在组织内皮下空间产生，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PTH诱导的主要反应基因，包括成骨细胞基因的转录调节因子Nurrl，这强烈表明高脂血症也可能干扰PTH的合成代谢作用。由于尽管治疗，高脂血症仍然普遍存在，了解其对骨代谢的影响可能对设计有效的甲状旁腺激素治疗至关重要。

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.