A novel regulating pathway in osteoclastogenesis and arthritic bone resorption

破骨细胞生成和关节炎骨吸收的新调节途径

• 批准号: 10091971
• 负责人: Kyung-Hyun Park-Min
• 金额: $ 37.44万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091971
• 关键词: Address; Arthritis; Attenuated; Binding; Biology; Bone Resorption; Bone remodeling; CSF1R gene; Calpain; Cell Nucleus; Cell surface; Cells; ChIP-seq; Cleaved cell; Complex; Coupling; DNA; Data; Defect; Deformity; Development; Diagnostic; Disease; Event; Exhibits; Feedback; Fibroblasts; Functional disorder; Gene Expression; Gene Expression Regulation; Generations; Goals; Immune; Impairment; In Vitro; Inflammatory; Inflammatory Arthritis; Interferon-beta; Investigation; Joints; Knowledge; Link; Lytic; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Malignant Neoplasms; Mediating; Metabolic Bone Diseases; Metastatic Neoplasm to the Bone; Morbidity - disease rate; Mus; Myelogenous; Names; Osteoblasts; Osteoclasts; Osteoporosis; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Process; Proteolysis; Receptor Signaling; Regulatory Pathway; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Surface; Symptoms; TNF gene; TNF-alpha converting enzyme; Testing; Therapeutic; Transgenic Mice; Work; attenuation; bone; bone erosion; bone loss; bone mass; chronic autoimmune disease; chronic inflammatory disease; clinical development; cytokine; experimental study; gamma secretase; genetic approach; in vivo; insight; mRNA Export; macrophage; member; novel; osteoclastogenesis; pathologic bone resorption; prevent; programs; receptor; release factor; response; therapeutically effective; transcriptome; transcriptomics

Osteoclasts are large myeloid-derived multinucleated cells primarily responsible for bone resorption. Dysregulation of osteoclast differentiation can result in net bone resorption and is key to the pathophysiology of rheumatoid arthritis, osteoporosis, and lytic bone metastasis. Thus, understanding the mechanism of osteoclast differentiation is of great therapeutic importance for nearly all forms of metabolic bone disease. Our long-term goals are 1) to elucidate a role of the newly described regulatory pathway in osteoclastogenesis and arthritic bone resorption and 2) to develop an effective and specific way to treat bone loss in RA. c-FMS, a receptor for M-CSF/ IL-34, transduces essential signals for the differentiation of osteoclasts and macrophages. Aberrant expression of c-FMS (or M-CSF) has been linked to exacerbation of diseases such as inflammatory arthritis and cancers. We have identified a novel regulatory pathway of c-FMS initiated by TACE (TNF-α converting enzyme). This pathway involves the coordinated, sequential cleavage of c-FMS by TACE, γ-secretase, and calpain, which results in the generation of intracellular domain cleavage fragments (referred to as FICD). Myeloid-specific TACE-deficient mice have high bone mass with decreased osteoclast numbers and ameliorate bone destruction in TNF-α induced arthritis in TNF transgenic (tg) mice. We found that FICD generation is critical for osteoclastogenesis, as enforced expression of FICD rescues the impaired osteoclastogenesis seen in TACE deficient cells. Thus, in addition to the well known role of c-FMS to activate conventional M-CSF signaling pathways as a surface receptor, c-FMS is also processed into the FICD that traffics into the nucleus, where it functions as a positive regulator of osteoclastogenesis. The existing paradigm is that shedding of c-FMS from the cell surface is a negative event related to loss of a signaling receptor. However, our study led us to discover that TACE-mediated shedding of c-FMS provides a positive signal for osteoclastogenesis. Here, we seek to build upon our novel findings to unravel the mechanisms by which the TACE/FICD axis regulates bone resorption, with a specific focus on inflammatory arthritis. Thus, we hypothesize that :1) TACE deficiency- mediated attenuation of arthritic bone resorption is, in part, due to lack of FICD, 2) Inhibition of the TACE/FICD axis ameliorates arthritic bone resorption, and 3) FICD targets the transcriptomic program in osteoclastic bone resorption. Our specific aims are 1) to investigate the underlying mechanisms behind how the TACE/FICD axis regulates pathological bone resorption in TNF-tg mice and 2) to elucidate the mechanism by which the TACE/FICD axis regulates osteoclastogenesis by identifying the direct pathways/targets of FICD. We anticipate that a better understanding of the diverse roles of this TACE/c- FMS/FICD pathway will advance our understanding of fundamental osteoclast biology, and targeting the TACE/FICD axis may provide new ways to attenuate bone resorption in inflammatory arthritis.

破骨细胞是主要负责骨形成的大型骨髓源性多核细胞 再吸收破骨细胞分化的失调可导致净骨吸收，并且是破骨细胞分化的关键。 类风湿性关节炎、骨质疏松症和溶解性骨转移的病理生理学。因此，了解 破骨细胞分化的机制对于几乎所有形式的代谢性疾病都具有重要的治疗意义。 骨病我们的长期目标是：1）阐明新描述的调控途径在以下方面的作用： 破骨细胞生成和关节炎性骨吸收，以及2）开发有效和特异性的治疗方法 RA中的骨丢失。c-FMS是M-CSF/ IL-34的受体，转导分化的基本信号， 破骨细胞和巨噬细胞。c-FMS（或M-CSF）的异常表达与急性加重有关 例如炎症性关节炎和癌症。我们已经确定了一种新的调节途径， TACE（TNF-α转化酶）启动c-FMS。这条途径涉及协调的，顺序的 TACE、γ-分泌酶和钙蛋白酶切割c-FMS，导致细胞内 结构域切割片段（称为FICD）。骨髓特异性TACE缺陷小鼠具有高骨密度， TNF-α诱导的关节炎中破骨细胞数量减少并改善骨破坏的肿块， TNF转基因（tg）小鼠。我们发现FICD的产生对于破骨细胞的生成至关重要， FICD的表达挽救了在TACE缺陷细胞中观察到的受损的破骨细胞生成。因此在 除了众所周知的c-FMS激活常规M-CSF信号通路作为表面活性剂的作用外， 受体，c-FMS也被加工成FICCD，FICCD进入细胞核，在那里它作为一个 破骨细胞生成的正调节因子。现有的范例是c-FMS从细胞脱落 表面是与信号受体的损失相关的负面事件。然而，我们的研究发现， TACE介导的c-FMS脱落为破骨细胞生成提供了阳性信号。在这里，我们寻求 以我们的新发现为基础，阐明TACE/FICD轴调节骨的机制 吸收，特别关注炎症性关节炎。因此，我们假设：1）TACE缺陷- 介导的关节炎骨吸收减弱部分是由于缺乏FICD，2）抑制 TACE/FICD轴改善关节炎骨吸收，3）FICD靶向转录组程序， 骨吸收我们的具体目标是：1）调查背后的潜在机制 TACE/FICD轴如何调节TNF-tg小鼠的病理性骨吸收，2）阐明 TACE/FICD轴通过识别直接的 FICD的途径/靶点。我们预计，更好地理解这种TACE/c的不同作用- FMS/FICD通路将促进我们对破骨细胞基本生物学的理解，并靶向 TACE/FICD轴可能为减轻炎症性关节炎骨吸收提供新的途径。