Negative Regulation of Osteoclastogenesis

髓系破骨细胞是唯一有效的骨吸收细胞。许多病理情况 与过度的骨吸收和骨丢失相关的特征是 破骨细胞生成。这个项目的长期目标是阐明新的分子途径和 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。炎症通过以下途径减少骨量 抑制成骨细胞介导的骨形成，同时强烈促进骨吸收 增强破骨细胞的分化和骨吸收功能。因此，炎症导致局部 类风湿性关节炎(RA)、牙周炎等疾病炎症部位的骨侵蚀/骨溶解 感染和骨科种植体周围松动。炎症部位也以缺氧为特征， 其增强RANKL诱导的破骨细胞生成的机制大多不为人知。病理性骨 在炎性/缺氧环境中的丢失，如RA滑膜，对标准的抗吸收药物具有抵抗力 新疗法和新疗法的开发是一个重要的未得到满足的医疗需求。 基于我们的总体假设，即增强抑制机制代表着 在先前的项目中，有吸引力的替代治疗方法来抑制病理性骨吸收 期间，我们研究了抑制代谢和表观遗传途径的机制，这些途径对 破骨细胞生成，与炎症性骨丢失有关。我们发现干扰素-，很好地被证实为 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， 导致关键破骨细胞增强子和启动子上染色质和组蛋白标记的重塑 基因。我们发现了破骨细胞的一种新的细胞内在负调控因子COMMD1，它通过 抑制NF-B信号转导和诱导合成代谢途径 破骨细胞生成。增加COMMD1表达的等位基因变异与骨质减少相关 RA患者的丢失和Commd1的髓系缺失导致炎症性骨丢失增加 模特们。COMMD1被低氧灭活，表明这种抑制机制在 低氧部位，如RA滑膜，会导致病理性骨丢失。外在的和内在的 负性调节因子干扰素-和COMMD1相互融合抑制其表达和功能 对于诱导破骨细胞代谢基因和途径具有重要作用的转录因子。这些结果 确定新的抑制机制，我们将对其进行表征，以获得可用于 开发抑制破骨细胞生成和病理性骨吸收的新方法 这些抑制机制在治疗上。

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.