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（由申请人提供）：本申请涉及项目公告 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促进骨关节炎（OA）的发生和进展。关节炎影响着数以千万计的美国人，但由于我们对 OA 的了解不足，目前还没有经过证实的疾病缓解方法。 OA 的特点是软骨基质遭到破坏，而软骨基质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（关节软骨的独特细胞类型）会发生类似于肥大样变化的变化。在某种程度上，这些变化包括导致基因表达和细胞功能异常的 DNA 甲基化状态的改变，我们发现在体内 OA 软骨细胞中观察到的异常基因表达与 DNA 甲基化的改变有关。概括发育事件，不适当地导致关节软骨细胞进入肥大样状态。在这个项目中，我们将利用亚硫酸氢盐转化的增强还原表示来分析生长板软骨细胞的 DNA 甲基化状态，并定义与软骨细胞肥大相关的 DNA 甲基化模式。然后，我们将通过 RNA 测序评估与进展中发生的 DNA 甲基化和基因表达变化的相似性。使用人类 OA 软骨样本和手术诱导 OA 的小鼠模型，这些方法将使我们能够定义导致 OA 疾病发生和进展的表观基因组改变，最终，我们的实验的成功完成应该会导致 OA 疾病的阶段。通过针对表观基因组调控中疾病相关的改变，开发早期 OA 的新治疗策略。

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