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Role of HDAC7 in Osteoclast Differentiation

HDAC7 在破骨细胞分化中的作用

基本信息

批准号：
9256437
负责人：
ERIC D JENSEN
金额：
$ 39.23万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256437
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 Genetic Transcription Goals Histone Deacetylase Histone Deacetylase Inhibitor Impairment In Vitro Knock-out Knockout Mice Knowledge Lead Macrophage Colony-Stimulating Factor Malignant Neoplasms Mediating Modeling Molecular Multiprotein Complexes Mus Osteoblasts Osteoclasts Osteogenesis Osteolytic Osteoporosis Outcome Pathogenesis Pathologic Pathway interactions Periodontal Diseases Periodontitis Phenotype Phosphorylation Physiology Population Prevention therapy Preventive Intervention Proteins Recruitment Activity Regulation Regulatory Pathway Reporting Repression Research Role Signal Transduction TRANCE protein Testing Therapeutic Therapeutic Intervention Work bone loss cathepsin K enhancing factor experience experimental study gene repression improved in vivo inhibitor/antagonist innovation microphthalmia-associated transcription factor mitogen-activated protein kinase p38 mouse model novel novel strategies novel therapeutics osteoclastogenesis overexpression prevent progenitor promoter public health relevance skeletal transcription factor

项目摘要

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（由申请人提供）：对于许多非常常见的临床病症，包括骨质疏松症、转移性骨疾病、牙周炎和关节炎，需要减少破骨细胞骨丢失的新方法;相反，需要增加破骨细胞功能的策略来纠正包括骨硬化症在内的病症中骨吸收的缺乏。为了提高我们在临床上操纵破骨细胞活性的能力，需要更深入地了解控制其生理学的分子机制。我们已经确定组蛋白去乙酰化酶7（HDAC 7）作为破骨细胞分化的负调节因子，对新疗法的开发具有潜在意义。虽然其他HDAC的抑制损害破骨细胞生成，但初步研究揭示了HDAC 7在破骨细胞中的独特功能。HDAC 7的抑制增强了它们的形成，而它们的形成被HDAC 7的过表达损害。使用靶向破骨细胞的LysM-Cre小鼠，我们有初步数据表明，在3个月大时，HDAC 7缺失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HDAC 7和MITF转录因子之间的RANKL调节的相互作用介导的。这些结果表明，骨细胞中HDAC 7活性的降低可能导致病理性骨丢失，而HDAC 7的刺激可能代表临床上减少骨丢失的新策略。然而，目前对HDAC 7在破骨细胞中的功能的不完全理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HDAC 7是破骨细胞分化的负调节因子，并通过抑制MITF和PU.1（以及潜在的其他转录因子）的激活发挥作用。通过p38 MAP激酶途径的RANKL信号传导破坏了这些抑制性相互作用，使破骨细胞基因有效表达和随后的分化成为可能。我们将通过三个特定目的来检验这一假设：1）表征破骨细胞祖细胞中HDAC 7条件性敲除的体内表型和细胞效应; 2）表征HDAC 7调节破骨细胞分化的分子机制; 3）确定RANKL调节MITF/PU.1-HDAC 7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，推进对异常骨丢失的改善治疗策略的研究，并最终导致更好的临床结局。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Histone deacetylase 5 is a phosphorylation substrate of protein kinase D in osteoclasts.

DOI：
10.1016/j.bone.2022.116393
发表时间：
2022-06
期刊：
BONE
影响因子：
4.1
作者：
Meyers, Carina Mello Guimaraes;Burciaga, Samuel D.;Faulkner, Bora;Kazemi, Parandis;Cohn, Jacob M.;Mansky, Kim C.;Jensen, Eric D.
通讯作者：
Jensen, Eric D.

Epigenetic Regulators Involved in Osteoclast Differentiation.