Impact of the DNA Methylome in Chondrocyte Hypertrophy in Osteoarthritis

DNA 甲基化对骨关节炎软骨细胞肥大的影响

基本信息

批准号：
9324109
负责人：
Miguel Otero
金额：
$ 22万
依托单位：
HOSPITAL FOR SPECIAL SURGERY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324109
关键词：
Address Adult Affect American Arthritis Automobile Driving Binding Cartilage Cartilage Matrix Cell physiology Cellular Structures Characteristics Chondrocytes Collagen Type X DNA DNA Methylation DNA Sequence Alteration Data Data Set Degenerative polyarthritis Development Disease Disease Marker Enzymes Epigenetic Process Epiphysial cartilage Etiology Event Extracellular Matrix GDF5 gene Gene Abnormality Gene Expression Gene Expression Profile Generations Genes Genetic Fingerprintings Genetic Transcription Histologic Human Hypertrophy In Situ In Vitro Inflammatory Joints Lead Link Mediating Methylation Modeling Mus NIH Program Announcements Nature Pain Patients Pattern Phenotype Promoter Regions Regulation Sampling Site Specimen Surface Surgical Models Testing Time Transcription Coactivator articular cartilage bisulfite cell type collagenase 3 cytokine demethylation disability epigenome epigenomics experimental study genome-wide in vivo innovation insight methylation pattern methylome mouse model novel novel therapeutics overexpression promoter public health relevance targeted treatment therapeutic evaluation transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): This application addresses the program announcement R21 PA-13-303. Our focus is on understanding how epigenetic mechanisms controlling developmental patterns contribute to the onset and progression of osteoarthritis. While osteoarthritis (OA) is the most prevalent form of arthritis, affecting tens of millions of Americans, relatively little is known about the mechanism(s) implicated in the early stages of the disease. As a consequence of our poor understanding of OA, there is no proven disease-modifying therapy available. OA is characterized by the destruction of the cartilage matrix, which is essential for maintaining the integrity of the joint surfaces. In OA disease, chondrocytes, the unique cell type of articular cartilage, undergo hypertrophic- like changes that resemble patterns observed during development. To some extent, those changes comprise alterations of the DNA methylation status that lead to abnormal gene expression and cell function. We hypothesize that the abnormal gene expression observed in OA chondrocytes in vivo relates to alterations in DNA methylation that recapitulate developmental events, inappropriately leading articular chondrocytes to a hypertrophic-like state. In this project, we will utilize Enhanced Reduced Representation of Bisulfite Conversion to profile the DNA methylation status of growth plate chondrocytes, and to define DNA methylation patterns associated with chondrocyte hypertrophic differentiation and linked to changes in gene expression, assessed by RNA sequencing. We will then establish parallels with alterations in DNA methylation and gene expression that occur at progressive stages of OA disease, using human OA cartilage samples and a mouse model of surgically-induced OA. These approaches will allow us to define epigenomic alterations that lead to OA disease initiation and progression. Ultimately, the successful completion of our experiments should lead to the development of novel therapeutic strategies for early OA by targeting disease-related alterations in epigenomic regulation.

描述（由应用程序提供）：此应用程序地址计划公告R21 PA-13-303。我们的重点是了解控制发育模式的表观遗传机制如何有助于骨关节炎的发作和发展。尽管骨关节炎（OA）是关节炎最普遍的形式，影响了数千万美国人，但对疾病早期实施的机制知之甚少。由于我们对OA的了解不足，因此没有可靠的疾病改良疗法可用。 OA的特征是软骨基质的破坏，这对于维持关节表面的完整性至关重要。在OA疾病中，软骨细胞是关节软骨的独特细胞类型，经历了类似于发育过程中观察到的模式的肥厚性变化。在某种程度上，这些变化完全改变了DNA甲基化状态，这使我们假设我们假设在体内OA软骨细胞中观察到的绝对基因表达与DNA甲基化的改变，从而缩减了发育事件的改变，这些事件概括了不适当的领先的关节膜状软骨细胞对超强型状态状态。在这个项目中，我们将利用硫酸含石转化率的减少表示形式，以介绍生长板软骨细胞的DNA甲基化状态，并定义与软骨细胞肥大性分化相关的DNA甲基化模式，并与基因表达的变化相关，并通过RNA测序评估了基因表达的变化。然后，我们将使用人OA软骨样品和手术诱导的OA的小鼠模型建立与DNA甲基化和基因表达改变的相似之处。这些方法将使我们能够定义导致OA疾病启动和进展的表观基因组改变。最终，我们的实验的成功完成应通过靶向与疾病相关的表观基因组调节的改变，从而发展出新的OA治疗策略。

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）

Changes in DNA methylation accompany changes in gene expression during chondrocyte hypertrophic differentiation in vitro.

DOI：
10.1111/nyas.14494
发表时间：
2021-04
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Singh P;Lessard SG;Mukherjee P;Rourke B;Otero M
通讯作者：
Otero M

Transcriptomic and epigenomic analyses uncovered Lrrc15 as a contributing factor to cartilage damage in osteoarthritis.

DOI：
10.1038/s41598-021-00269-8
发表时间：
2021-10-26
期刊：
Scientific reports
影响因子：
4.6
作者：
Singh P;Wang M;Mukherjee P;Lessard SG;Pannellini T;Carballo CB;Rodeo SA;Goldring MB;Otero M
通讯作者：
Otero M