The role of class II histone deacetylases in PTH signaling in osteocytes

性状（由申请方提供）：甲状旁腺激素（PTH）是一种肽类激素，在钙代谢中起主要作用。此外，每日重组形式的PTH（1-34，teriparlitazone）是唯一FDA批准的合成代谢性骨质疏松症治疗。到目前为止，我们还没有完全了解特立哌酮合成代谢作用的详细细胞和分子机制。PTH受体在骨细胞中表达，并且骨细胞中的PTH信号传导可能对于特立哌酮刺激净骨产生的能力至关重要。硬化蛋白是成骨细胞骨形成的骨细胞源性抑制剂，其表达被PTH下调。硬化蛋白是治疗骨质疏松症的一个新的药物靶点，PTH对硬化蛋白的抑制可能是特立普治疗效果的重要机制之B。该提案旨在研究骨细胞中PTH信号传导导致sclerostin下调的分子机制。我们的假设是，IIa类组蛋白脱乙酰酶（HDAC）蛋白质在PTH受体和硬化素抑制之间的途径中发挥重要作用。我们计划使用体外和体内方法的组合来研究IIa类HDAC在该途径中的作用。首先，将使用shRNA介导的基因沉默在新的骨细胞细胞系中操纵IIa类HDAC的水平，该细胞系显示出稳健的PTH依赖性硬化蛋白下调。接下来，将进行详细的机制研究，以了解IIa类HDAC如何在从PTH到sclerostin下调的途径中发挥作用。最后，将研究骨细胞中缺乏IIa类HDAC的小鼠，以确定PTH是否需要IIa类HDAC来降低体内硬化蛋白水平。这些研究将提供关于特立哌酮骨合成代谢作用的骨细胞信号通路的关键数据。此外，对这些途径的更好理解可能会导致骨质疏松症新疗法的开发。

DESCRIPTION (provided by applicant): Parathyroid hormone (PTH) is a peptide hormone with a major role in calcium metabolism. In addition, a daily recombinant form of PTH (1-34, teriparatide) is the only FDA-approved anabolic osteoporosis treatment. To date, we do not fully understand the detailed cellular and molecular mechanism of teriparatide's anabolic effect. PTH receptors are expressed in osteocytes, and PTH signaling in osteocytes is likely to be vital for the ability of teriparatide to stimulate net bone production. Sclerostin is an osteocyte-derived inhibitor of bone formation by osteoblasts whose expression is down-regulated by PTH. Sclerostin is a novel drug target for osteoporosis, and sclerostin inhibition by PTH is likely to b an important mechanism underlying the teriparatide treatment effect. This proposal aims to study the molecular mechanisms whereby PTH signaling in osteocytes leads to sclerostin down-regulation. Our hypothesis is that class IIa histone deacetylase (HDAC) proteins play an essential role in the pathway between the PTH receptor and sclerostin inhibition. We plan to study the role of class IIa HDACs in this pathway using a combination of in vitro and in vivo approaches. First, levels of class IIa HDACs will be manipulated using shRNA-mediated gene silencing in a novel osteocytes cell line which displays robust PTH-dependent sclerostin down-regulation. Next, detailed mechanistic studies will be performed to understand how class IIa HDACs function in the pathway leading from PTH to sclerostin down-regulation. Finally, mice lacking class IIa HDACs in osteocytes will be studied to determine if class IIa HDACs are required for PTH to reduce sclerostin levels in vivo. These studies will provide key data regarding the signaling pathways in osteocytes underlying teriparatide's osteoanabolic effect. In addition, an improved understanding of these pathways may lead to the development of novel therapies for osteoporosis.