The Crosstalk between MYC and Metabolism during Osteoclastogenesis

破骨细胞生成过程中 MYC 与代谢之间的串扰

• 批准号: 9356304
• 负责人: Kyung-Hyun Park-Min
• 金额: $ 38.72万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356304
• 关键词: Affect; Animal Model; Antibodies; Biology; Bone Diseases; Bone Resorption; Bone remodeling; Cell Lineage; Cells; Cellular Metabolic Process; ChIP-seq; Chronic; Clinic; Complex; Data; Development; Diagnostic; Disease; FRAP1 gene; Fibroblasts; Genes; Genetic Transcription; Goals; Homeostasis; Hyperactive behavior; Immune; In Vitro; Inflammation; Inflammatory; Joints; Knowledge; Lead; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Nature; Osteoclasts; Outcome; Ovariectomy; Pathologic; Patients; Pharmacology; Phenotype; Physiological; Play; Prevention; Proto-Oncogene Proteins c-myc; Regulation; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Symptoms; TNF gene; TNFSF11 gene; Testing; Therapeutic; Therapeutic Intervention; Translations; Work; bone; bone erosion; bone loss; bone mass; cell growth; clinical development; cytokine; experience; improved; in vivo; inhibitor/antagonist; innovation; insight; new therapeutic target; novel; osteoclastogenesis; osteoimmunology; pathologic bone resorption; precursor cell; prevent; programs; substantia spongiosa; transcriptomics

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which immune cells and synovial fibroblasts produce pro-inflammatory cytokines and drive an inflammatory state leading to the destruction of affected joints. Bone erosion is a diagnostic hallmark of RA and commonly precedes the development of clinical symptoms. Osteoclasts are myeloid lineage cells that effectively resorb bone and are directly responsible for bone erosion and morbidity in RA. Thus, our overall hypothesis is that a better understanding of the regulation of osteoclast differentiation and activity is likely to yield novel targets for therapies that limit pathological bone resorption. We have found that the transcription factor MYC and MYC-dependent transcriptional programs are activated by RANKL during early osteoclast differentiation. Although MYC has been implicated in osteoclastogenesis, the precise mechanisms by which MYC affects the homeostasis and function of osteoclasts remain largely unexplored. We have found that MYC is required for osteoclast differentiation and regulates the genes that are associated with metabolism and translation during osteoclastogenesis. Interestingly, both MYC and NFATc1 expression are significantly elevated in synovial osteoclast precursors (OCPs) from patients with RA that have a greater potential for differentiating into osteoclasts. OCPs are thought to reprogram their metabolism to meet the energy demands of osteoclasts, which must fuse into multinucleated cells and synthesize molecules to resorb bone. However, the contribution of metabolic pathways to osteoclast differentiation and the key molecule that regulates metabolic reprogramming are not well understood. Therefore, we hypothesize that MYC plays an important role in RANKL-induced metabolic reprogramming and MYC is one of the major contributors to generate hyperactive osteoclasts in inflammatory bone diseases by altering specific metabolic pathways. To test our hypothesis, we proposed three specific aims :1) to characterize the role of MYC in osteoclastogenesis in vivo, 2) to identify the molecular mechanisms underlying the regulation and function of MYC, and 3) to investigate mechanisms by which MYC regulates metabolic reprogramming in osteoclasts. This study will advance our understanding of the role of MYC in osteoclast differentiation, the role of metabolic reprogramming occurring during osteoclast differentiation, and the crosstalk between MYC and metabolic reprogramming during osteoclastogenesis. In addition, as therapies directly targeting MYC activation are not presently available in the clinic, identification of effector molecule(s) downstream of MYC that play important roles in osteoclast differentiation may serve as novel therapeutic targets for the treatment and prevention of pathological bone resorption. Therefore, the overall impact of this project is to yield insights that will not only broaden our understanding of the role of MYC in the field of osteoimmunology, but can also be exploited to develop therapeutic interventions to suppress bone resorption by hyperactive osteoclasts resulting from deregulated MYC expression.

类风湿性关节炎（RA）是一种免疫细胞和滑膜成纤维细胞的慢性炎症性疾病