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Epigenetic Regulation of Bone Regeneration in Inflammatory Disease

炎症性疾病中骨再生的表观遗传调控

基本信息

批准号：
10192663
负责人：
Jie Shen
金额：
$ 51.68万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10192663
关键词：
Ablation Address Affect Binding Bone Regeneration Bone callus Cell Differentiation process Cells Chondrocytes Chronic Clinical Clinical Research Complex DNA Methylation DNA Modification Methylases DNMT3B gene Data Defect Diabetes Mellitus Disease Elderly Enzymes Epigenetic Process Event Fibroblasts Fracture Fracture Healing Genetic Genetic Transcription Goals Human Impaired healing Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Knowledge Mediating Mesenchymal Stem Cells Methylation Molecular Mus Orthopedics Osteitis Osteoblasts Pathway interactions Patients Pharmacology Population Process Publications Rheumatoid Arthritis Role Series Signal Transduction Smoking Testing Therapeutic Intervention Time Transgenic Mice Trauma United States Up-Regulation Work bone fracture repair bone quality cell type chronic inflammatory disease cytokine diabetic epigenetic regulation epigenome fracture risk gain of function healing in vivo inhibitor/antagonist loss of function new therapeutic target notch protein novel older patient osteoprogenitor cell progenitor promoter protective effect repaired response stem cell proliferation systemic inflammatory response therapeutic candidate tool

项目摘要

ABSTRACT Inflamed bone fracture poses a significant clinical problem. In the United States, approximately 1.6 million bone fractures encounter prolonged healing or non-union each year, among which, the major population bearing with these clinical complications are patients with inflammatory conditions, e.g, elder patients, smoking, diabetic or rheumatoid arthritis (RA) patients. In these patients, the fracture risk is increased due to the poor bone quality, highlighting the potential deleterious role of chronic systemic inflammation in fracture repair. The overarching hypothesis of this proposal is that under inflammatory conditions, NF-κB, the principal mediator of inflammation, induces Rbpjκ expression through downregulating Dnmt3b and its DNA methylation activity. We further hypothesize that Dnmt3b GOF or Rbpjκ inhibition restores MPC differentiation and chondrocyte maturation that are reduced by inflammation during fracture repair. This hypothesis is supported by our preliminary data wherein we show that Dnmt3b is highly expressed in fracture callus during fracture repair and Dnmt3b is the major DNA methyltransferase (Dnmt) responsive to cytokine in MPCs and chondrocytes. Relevant to our proposal, we provide evidence that inflammatory signals inhibit Dnmt3b in MPCs and chondrocytes in an NF-κB-dependent manner. Consistently, mice with Dnmt3b loss-of-function (LOF) in MPCs and chondrocytes display delayed fracture repair; and Dnmt3b gain-of-function (GOF) in MPCs or chondrocytes shows protective effect from inflammation in vitro and accelerates fracture repair in mice. Mechanistically, MPC differentiation defect mediated by inflammation and Dnmt3b LOF coincide with upregulation of Rbpjκ in MPCs and Rbpjκ inhibition can restore differentiation capacity in vitro. In vitro mechanistic studies and in vivo LOF and GOF approaches will be used to modulate IKK2, Dnmt3b and Rbpjκ expression in MPCs and chondrocytes to dissect its effects during fracture repair process. Three main Specific Aims are proposed. Specific Aim 1 will delineate the effect of constitutively active NF-κB signaling (IKK2ca), as the principal molecular driver of inflammation, on Dnmt3b expression and fracture repair. Specific Aim 2 will establish the effect of Dnmt3b GOF in MPCs and chondrocytes on accelerating fracture repair. Specific Aim 3 will delineate the mechanism by which Dnmt3b regulates downstream target, Rbpjκ, during fracture repair. This work will enhance our understanding of mechanisms by which systemic inflammation (via the NF-κB pathway) affects the fracture healing process through Dnmt3b and identify downstream targets of Dnmt3b (such as Rbpjκ) as novel candidates for therapeutic intervention.

摘要