Role of HDAC7 in Osteoclast Differentiation

描述（由申请人提供）：减少破骨细胞骨质流失的新方法需要用于许多非常常见的临床疾病，包括骨质疏松症，转移性骨病，牙周炎和关节炎；相反，增加破骨细胞功能的策略对于纠正骨质疏松等情况下的骨吸收不足是必要的。为了提高我们在临床上操纵破骨细胞活性的能力，将需要对控制其生理的分子机制有更深入的了解。我们已经确定了组蛋白去乙酰化酶7 （HDAC7）作为破骨细胞分化的负调节因子，这对新疗法的发展具有潜在的意义。虽然抑制其他hdac会损害破骨细胞的形成，但初步研究揭示了HDAC7在破骨细胞中的独特功能。抑制HDAC7可以促进它们的形成，而过表达HDAC7则会损害它们的形成。使用LysM-Cre小鼠，其目标是破骨细胞，我们有初步的数据表明，在3个月大时，hdac7缺失的小鼠由于破骨细胞生成增强而骨质减少。进一步的数据表明，这些作用是通过rankl调控的HDAC7和MITF转录因子之间的相互作用介导的。这些结果表明，破骨细胞中HDAC7活性的降低可能导致病理性骨质流失，而刺激HDAC7可能是临床上减少骨质流失的一种新策略。然而，目前对HDAC7在破骨细胞中的功能的不完全了解限制了这种诊断或治疗方法的合理发展。我们的中心假设是HDAC7是破骨细胞分化和功能的负调节因子，通过抑制MITF和PU.1（以及潜在的其他转录因子）的激活。RANKL信号通过p38 MAP激酶途径破坏这些抑制性相互作用，使破骨细胞基因高效表达和随后的分化成为可能。我们将通过三个具体目的来验证这一假设：1)表征破骨细胞祖细胞中条件敲除HDAC7的体内表型和细胞效应；2)表征HDAC7调控破骨细胞分化的分子机制；3)确定RANKL调控MITF/PU的机制及生物学意义。1-HDAC7交互。这些目标的完成将显著增加我们对破骨细胞独特调控途径的认识，推进对异常骨质流失的改进治疗策略的研究，并最终导致更好的临床结果。

DESCRIPTION (provided by applicant): Novel approaches to reduce osteoclastic bone loss are needed for a number of exceedingly common clinical conditions including osteoporosis, metastatic bone disease, periodontitis, and arthritis; conversely, strategies to increase osteoclast function are necessary to correct the lack of bone resorption in conditions including osteopetrosis. To improve our ability to clinically manipulate osteoclast activity will require a deeper understanding of the molecular mechanisms that govern their physiology. We have identified histone deacetylase 7 (HDAC7) as a negative regulator of osteoclast differentiation that has potential implications for the development of new therapies. While inhibition of other HDACs impairs osteoclastogenesis, preliminary studies reveal a unique function for HDAC7 in osteoclasts. Suppression of HDAC7 enhances their formation, while their formation is impaired by overexpression of HDAC7. Using the LysM-Cre mouse, which targets osteoclasts, we have preliminary data demonstrating that at 3 months of age HDAC7-null mice are osteopenic due to enhanced osteoclastogenesis. Further data indicate that these effects are mediated through RANKL-regulated interactions between HDAC7 and the MITF transcription factor. These results suggest that reduced HDAC7 activity in osteoclastic cells may contribute to pathological bone loss, whereas stimulation of HDAC7 might represent a novel strategy to clinically reduce bone loss. However, the current incomplete understanding of HDAC7's function in osteoclasts limits the rational development of such diagnostic or therapeutic approaches. Our central hypothesis is that HDAC7 is a negative regulator of osteoclast differentiation and functions by repressing the activation of MITF and PU.1 (and potentially other transcription factors). RANKL signaling through the p38 MAP kinase pathway disrupts these repressive interactions, enabling efficient osteoclast gene expression and subsequent differentiation. We will test this hypothesis with three specific aims: 1) Characterize the in vivo phenotype and cellular effects of conditional knockout of HDAC7 in osteoclast progenitors; 2) Characterize the molecular mechanisms by which HDAC7 regulates osteoclast differentiation; and 3) Determine the mechanism and biological significance of RANKL regulation of MITF/PU.1-HDAC7 interaction. Completion of these aims will significantly increase our knowledge concerning a unique regulatory pathway in osteoclasts, advance the search for improved therapeutic strategies for aberrant bone loss and ultimately lead to be better clinical outcomes.