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Negative Regulation of Osteoclastogenesis

破骨细胞生成的负调控

基本信息

批准号：
10112883
负责人：
Lionel B Ivashkiv
金额：
$ 41.8万
依托单位：
HOSPITAL FOR SPECIAL SURGERY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-08 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112883
关键词：
Biological Assay Bone Resorption Bone remodeling Cell Lineage Cells Coupled Coupling Development Disease Enhancers Environment Enzymes Epigenetic Process Gene Expression Profile Generations Genes Goals Histones Human Hypoxia Implant Infection Inflammation Inflammatory Interferons Interleukin-1 Knowledge Link MAP Kinase Gene Mediating Medical Metabolic Metabolic Pathway Metabolism Modeling Molecular Musculoskeletal Myelogenous Orthopedics Osteoblasts Osteoclasts Osteogenesis Osteolysis Pathologic Pathway interactions Patients Periodontitis Phase Physiological Regulation Resistance Rheumatoid Arthritis Signal Induction Signal Transduction Site Synovial Membrane TNF gene TNFSF11 gene Therapeutic Transcription Factor AP-1 Work base bone bone erosion bone loss bone mass chromatin modification chromatin remodeling cofactor cytokine epigenome epigenomics genetic variant in vivo Model inflammatory bone loss novel strategies novel therapeutic intervention osteoclastogenesis pathologic bone resorption promoter therapeutic target transcription factor

项目摘要

Myeloid lineage osteoclasts are the sole effective bone-resorbing cells. Many pathological conditions associated with excessive bone resorption and bone loss are characterized by excessive osteoclastogenesis. The long term goals of this project are to elucidate new molecular pathways and mechanisms that suppress osteoclastogenesis, with the associated goal of using this information to develop new therapeutic approaches to suppress pathological bone resorption. Inflammation is an important driver of pathological bone loss. Inflammation decreases bone mass by suppressing osteoblast-mediated bone formation, and concomitantly strongly promoting bone resorption by increasing the differentiation and bone-resorbing function of osteoclasts. Thus, inflammation induces local bone erosion/osteolysis at inflammatory sites in diseases such as rheumatoid arthritis (RA), periodontitis, infections, and orthopedic peri-implant loosening. Inflammatory sites are also characterized by hypoxia, which potentiates RANKL-induced osteoclastogenesis by mostly unknown mechanisms. Pathological bone loss in an inflammatory/hypoxic environment such as RA synovium is resistant to standard anti-resorptive therapies, and development of new treatments represents an important unmet medical need. Based on our overarching hypothesis that augmenting inhibitory mechanisms represents an attractive alternative therapeutic approach to suppress pathologic bone resorption, in the previous project period we investigated mechanisms that suppress metabolic and epigenetic pathways important for osteoclastogenesis and are relevant for inflammatory bone loss. We found that IFN-, well established to restrain bone loss at inflammatory sites, remodeled the epigenome of human osteoclast precursors, resulting in remodeling of chromatin and histone marks at enhancers and promoters of key osteoclast genes. We discovered a new cell-intrinsic negative regulator of osteoclasts, COMMD1, which works by suppressing NF-B signaling and the induction of anabolic metabolic pathways important for osteoclastogenesis. Allelic variants that increase COMMD1 expression are associated with decreased bone loss in RA patients, and myeloid deletion of Commd1 resulted in increased bone loss in inflammatory models. COMMD1 is inactivated by hypoxia, suggesting that abrogation of this inhibitory mechanism at hypoxic sites such as RA synovium contributes to pathological bone loss. The extrinsic and intrinsic negative regulators, IFN- and COMMD1 respectively, converged to suppress the expression and function of transcription factors important for induction of osteoclast metabolic genes and pathways. These results identify new inhibitory mechanisms, which we will characterize to obtain knowledge that can be used to develop new approaches to suppress osteoclastogenesis and pathologic bone resorption by augmenting these inhibitory mechanisms therapeutically.

髓系破骨细胞是唯一有效的骨吸收细胞。许多病理条件与过度的骨吸收和骨丢失相关的特征是过度的骨吸收和骨丢失。破骨细胞生成该项目的长期目标是阐明新的分子途径，抑制破骨细胞生成的机制，相关的目标是利用这些信息来开发抑制病理性骨吸收的新治疗方法。炎症是病理性骨丢失的重要驱动因素。炎症通过以下方式降低骨量：抑制成骨细胞介导的骨形成，并伴随强烈促进骨吸收，增加破骨细胞的分化和骨吸收功能。因此，炎症诱导局部例如类风湿性关节炎（RA），牙周炎，感染和矫形植入物周围松动。炎症部位也以缺氧为特征，其通过大多数未知的机制增强RANKL诱导的破骨细胞生成。病理性骨在炎症/缺氧环境中的损失，例如RA滑膜，对标准抗再吸收剂新疗法和新疗法的开发代表了重要的未满足的医疗需求。基于我们的总体假设，即增强抑制机制代表了一种在以前的项目中，有吸引力的替代治疗方法来抑制病理性骨吸收，在此期间，我们研究了抑制代谢和表观遗传途径的机制，破骨细胞生成并与炎性骨丢失有关。我们发现，IFN-γ，已被公认为抑制炎症部位的骨丢失，重塑人类破骨细胞前体的表观基因组，导致在关键破骨细胞的增强子和启动子处的染色质和组蛋白标记的重塑基因.我们发现了一种新的破骨细胞内源性负调节因子COMMD 1，它的作用机制是：抑制NF-κ B B信号传导和诱导合成代谢途径，破骨细胞生成增加COMMD 1表达的等位基因变体与骨密度降低相关在RA患者中，Commd 1的髓样缺失导致炎性骨丢失增加，模型缺氧会使COMMD 1失活，这表明缺氧时这种抑制机制的废除缺氧部位如RA滑膜导致病理性骨丢失。外在和内在负调节因子IFN-γ和COMMD 1分别会聚以抑制表达和功能对诱导破骨细胞代谢基因和途径重要的转录因子。这些结果确定新的抑制机制，我们将描述这些机制，以获得可用于开发新的方法来抑制破骨细胞生成和病理性骨吸收，这些抑制机制的治疗。