Role of HDAC7 in Osteoclast Differentiation

HDAC7 在破骨细胞分化中的作用

• 批准号: 8839712
• 负责人: ERIC D JENSEN
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839712
• 关键词: Age-Months; Albers-Schonberg disease; Apoptosis; Arthritis; Attenuated; Biological; Bone Diseases; Bone Marrow; Bone Resorption; Cells; Clinical; Clinical Trials; Data; Development; Diagnostic; Disease; Environment; Gene Expression; Gene Targeting; Genes; Goals; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; In Vitro; Knock-out; Knockout Mice; Knowledge; Lead; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteolytic; Osteoporosis; Outcome; Pathogenesis; Pathway interactions; Periodontal Diseases; Periodontitis; Phenotype; Phosphorylation; Physiology; Population; Prevention; Prevention therapy; Proteins; Recruitment Activity; Regulation; Regulatory Pathway; Relative (related person); Reporting; Repression; Research; Role; Signal Transduction; TRANCE protein; Testing; Therapeutic; Therapeutic Intervention; Work; bone loss; cathepsin K; enhancing factor; experience; gene repression; improved; in vivo; inhibitor/antagonist; innovation; microphthalmia-associated transcription factor; mitogen-activated protein kinase p38; mouse model; novel; novel strategies; osteoclastogenesis; overexpression; prevent; progenitor; promoter; protein complex; research study; skeletal; transcription factor

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.

描述(申请人提供)：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，都需要新的方法来减少破骨细胞性骨丢失；相反，增加破骨细胞功能的策略是必要的，以纠正包括骨质流失在内的情况下缺乏骨吸收的情况。为了提高我们在临床上操纵破骨细胞活性的能力，需要对支配其生理的分子机制有更深入的了解。我们已经确定组蛋白脱乙酰酶7(HDAC7)是破骨细胞分化的负调控因子，这对新疗法的开发具有潜在的意义。虽然抑制其他HDACs会损害破骨细胞的生成，但初步研究表明，HDAC7在破骨细胞中具有独特的功能。抑制HDAC7促进了它们的形成，而过表达HDAC7则阻碍了它们的形成。使用以破骨细胞为靶点的LysM-Cre小鼠，我们有初步数据表明，在3个月大的HDAC7基因缺失小鼠，由于增强的破骨细胞生成，是骨量减少的。进一步的数据表明，这些作用是通过RANKL调节的HDAC7和MITF转录因子之间的相互作用来介导的。这些结果表明，破骨细胞中HDAC7活性的降低可能是病理性骨丢失的原因之一，而刺激HDAC7可能是临床上减少骨丢失的一种新策略。然而，目前对HDAC7在破骨细胞中的S功能的不完全了解限制了此类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控因子，它通过抑制MITF和PU.1(以及潜在的其他转录因子)的激活来发挥作用。RANKL信号通过p38 MAP激酶通路破坏这些抑制相互作用，使破骨细胞基因高效表达和随后的分化。我们将通过三个具体的目标来验证这一假说：1)表征破骨细胞前体细胞中条件敲除HDAC7的表型和细胞效应；2)表征HDAC7调节破骨细胞分化的分子机制；3)确定RANKL调控MITF/PU.1-HDAC7相互作用的机制和生物学意义。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了解，推动寻找更好的治疗异常骨丢失的策略，并最终导致更好的临床结果。