RANKL and Inflammation-associated Bone Loss

RANKL 和炎症相关的骨丢失

• 批准号: 7687062
• 负责人: CHARLES A O'BRIEN
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687062
• 关键词: Activated Lymphocyte; Address; Adult; Alleles; Anti-Tumor Necrosis Factor Therapy; Attention; B-Lymphocytes; Bacterial Artificial Chromosomes; Bone Resorption; Bone remodeling; CD19 gene; Cell Line; Cells; Cis-Acting Sequence; Clinical; Complex; Cytokine Receptors; Dentition; Distal; Distant; Elements; Enhancers; Failure; Fibroblasts; Fracture; Gene Expression; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Health; Healthcare; Hematopoietic; Hormonal; Hormones; Inflammation; Inflammatory; Interleukin-6; Joints; Knock-out; Ligands; Lipopolysaccharides; Lymphocyte; Macrophage Colony-Stimulating Factor; Maps; Mediating; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Osteoclasts; Ovariectomy; Parathyroid gland; Patients; Periodontal Diseases; Process; Prosthesis; Proteins; Regulator Genes; Regulatory Element; Reporter; Rheumatism; Rheumatoid Arthritis; Role; Safety; Source; Stromal Cells; Supporting Cell; T-Cell Activation; T-Lymphocyte; TNF gene; Therapeutic; Tissues; Tooth Loss; Transcription Initiation Site; Veterans; Wild Type Mouse; abstracting; base; bisphosphonate; bone; bone loss; bone mass; bone strength; cell type; cost; cytokine; evidence base; in vivo; interest; mouse genome; mouse model; novel; novel strategies; receptor; receptor expression; tool

DESCRIPTION (provided by applicant): Project Summary/Abstract Loss of bone mass throughout the body, and especially adjacent to inflamed joints, is a major cause of morbidity and fracture in veterans with rheumatic diseases. Although bisphosphonates are sometimes used to protect bone in veterans with rheumatoid arthritis, there is no evidence-based indication that this therapeutic maneuver is effective. The long- term goal of the studies proposed in this application is to elucidate the mechanisms causing inflammation-associated bone loss. Osteoclasts are the only cells capable of degrading bone and RANKL is a protein produced by cells that support osteoclast differentiation that is essential for this process. Therefore, the studies proposed in this application seek to understand the mechanisms that control RANKL gene expression and identify the cell types that express it during inflammation by addressing the following hypothesis: inflammation- associated bone loss is due to stimulation of the RANKL gene in fibroblasts and stromal/osteoblastic cells, but not in activated T cells, and stimulation of RANKL expression is mediated by distant transcriptional regulatory elements. The studies in Specific Objective 1 will determine whether RANKL expression in lymphocytes contributes to bone loss in murine models of inflammation and sex steroid deficiency by deleting this gene specifically in T cells or B cells. Studies in Specific Objective 2 will identify the mechanisms by which inflammation stimulates RANKL gene transcription in stromal/osteoblastic cells and T lymphocytes by identifying the transcriptional responsive regions of the RANKL gene. Lastly, the studies in Specific Objective 3 will determine the role of a transcriptional enhancer of the RANKL gene, identified previously, in the bone loss associated with murine models of inflammation and sex steroid deficiency. It is important to note that the studies proposed in this application to elucidate the mechanisms causing inflammation-associated bone loss would also be relevant to other bone losing conditions such as periodontal tooth loss (the most common cause of adult loss of dentition), as well as the bone loss that occurs around prosthetic joints and results in their failure. In summary, the studies proposed in this Merit application are relevant to several major causes of localized as well as systemic bone loss and are thus important to the veterans patient health care mission. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care. Loss of bone mass throughout the body, and especially adjacent to inflamed joints, is a major cause of morbidity and fracture in veterans with rheumatic diseases. Although bisphosphonates are sometimes used to protect bone in veterans with rheumatoid arthritis, there is no evidence-based indication that this therapeutic maneuver is effective. TNF antagonists are another therapeutic option, but as many as 40% of rheumatoid arthritis patients do not respond to anti-TNF therapy. This, and the high cost and uncertain long- term safety of anti-TNF proteins, suggests that novel approaches are still required. Studies that address the mechanism behind the bone loss that occurs with inflammation are therefore of major clinical importance in the VA healthcare mission. Furthermore, studies proposed in this application to elucidate the mechanisms causing inflammation-associated bone loss would also be relevant to other bone losing conditions such as periodontal tooth loss (the most common cause of adult loss of dentition), as well as the bone loss that occurs around prosthetic joints and results in their failure. In summary, the studies proposed in this Merit application are relevant to several major causes of localized as well as systemic bone loss and are thus important to the veterans patient health care mission.

描述（由申请人提供）： 项目摘要/摘要全身骨质流失，尤其是发炎关节附近的骨质流失，是患有风湿性疾病的退伍军人发病和骨折的主要原因。尽管双磷酸盐有时用于保护患有类风湿性关节炎的退伍军人的骨骼，但没有证据表明这种治疗方法有效。本申请中提出的研究的长期目标是阐明导致炎症相关骨质流失的机制。破骨细胞是唯一能够降解骨骼的细胞，RANKL 是由支持破骨细胞分化的细胞产生的蛋白质，而破骨细胞分化对于这一过程至关重要。因此，本申请中提出的研究旨在通过解决以下假设来了解控制RANKL基因表达的机制并鉴定在炎症期间表达它的细胞类型：炎症相关的骨丢失是由于成纤维细胞和基质/成骨细胞中的RANKL基因的刺激引起的，而不是活化的T细胞中的RANKL基因的刺激，并且RANKL表达的刺激是由远程转录调节元件介导的。具体目标 1 中的研究将通过在 T 细胞或 B 细胞中特异性删除该基因，确定淋巴细胞中的 RANKL 表达是否会导致炎症和性类固醇缺乏的小鼠模型中的骨质流失。具体目标 2 中的研究将通过识别 RANKL 基因的转录反应区域来确定炎症刺激基质/成骨细胞和 T 淋巴细胞中 RANKL 基因转录的机制。最后，具体目标 3 中的研究将确定先前确定的 RANKL 基因转录增强子在与炎症和性类固醇缺乏的小鼠模型相关的骨质流失中的作用。值得注意的是，本申请中提出的旨在阐明导致炎症相关骨质流失的机制的研究也与其他骨质流失状况相关，例如牙周牙齿缺失（成人牙列缺失的最常见原因），以及发生在假体关节周围并导致其失败的骨质流失。总之，本优点申请中提出的研究与局部和全身性骨质流失的几个主要原因相关，因此对退伍军人患者的医疗保健任务很重要。 公共卫生相关性： 对退伍军人医疗保健的潜在影响。全身骨质流失，尤其是发炎关节附近的骨质流失，是患有风湿性疾病的退伍军人发病和骨折的主要原因。尽管双磷酸盐有时用于保护患有类风湿性关节炎的退伍军人的骨骼，但没有证据表明这种治疗方法有效。 TNF 拮抗剂是另一种治疗选择，但多达 40% 的类风湿性关节炎患者对抗 TNF 疗法没有反应。再加上抗 TNF 蛋白的高成本和不确定的长期安全性，表明仍然需要新的方法。因此，解决炎症引起的骨质流失背后机制的研究对于 VA 医疗保健任务具有重要的临床意义。此外，本申请中提出的旨在阐明导致炎症相关骨质流失的机制的研究也与其他骨质流失状况有关，例如牙周牙齿缺失（成人牙列缺失的最常见原因），以及发生在假体关节周围并导致其失败的骨质流失。总之，本优点申请中提出的研究与局部和全身性骨质流失的几个主要原因相关，因此对退伍军人患者的医疗保健任务很重要。