A novel regulating pathway in osteoclastogenesis and arthritic bone resorption

破骨细胞是大的髓系多核细胞，主要负责骨的形成。 再吸收。破骨细胞分化的失调可导致净骨吸收，是 类风湿性关节炎、骨质疏松症和骨转移的病理生理学。因此，理解 破骨细胞分化的机制对几乎所有形式的代谢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 破骨细胞生成与关节炎骨吸收；2)开发有效和特异的治疗方法 类风湿关节炎的骨丢失。C-FMS是M-CSF/IL-34的受体，转导细胞分化所必需的信号。 破骨细胞和巨噬细胞。C-FMS(或M-CSF)的异常表达与病情恶化有关 炎症性关节炎和癌症等疾病。我们已经确定了一种新的调控途径 由肿瘤坏死因子-α转换酶(TACE)启动的C-FMS。这条路径涉及协调的、顺序的 C-fms被血管紧张素转换酶、γ-分泌酶和钙蛋白酶切割，导致细胞内产生 结构域切割片段(称为FICD)。髓系特异性TACE缺陷小鼠有高骨量 肿瘤坏死因子-α诱导的关节炎大鼠破骨细胞数量减少和骨破坏减轻 肿瘤坏死因子转基因(TG)小鼠。我们发现，FICD的产生对于破骨细胞的形成是至关重要的，就像强制的那样 FICD的表达挽救了TACE缺陷细胞中受损的破骨细胞生成。因此，在 除了c-FMS激活传统的M-CSF信号通路作为表面的众所周知的作用之外 受体，c-fms也被加工成FICD，在FICD中，它作为一种 破骨细胞生成的正性调节因子。现有范例是c-FMS从细胞中脱落 表面是一种与信号受体丢失有关的负性事件。然而，我们的研究让我们发现 TACE介导的c-FMS的脱落为破骨细胞的形成提供了积极的信号。在这里，我们寻求 以我们的新发现为基础，解开TACE/FICD轴调节骨骼的机制 吸收，特别是炎症性关节炎。因此，我们假设：1)TACE缺乏- 关节炎骨吸收的介导性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靶向转录程序 破骨细胞性骨吸收。我们的具体目标是1)调查背后的潜在机制 TACE/FICD轴如何调节肿瘤坏死因子-甘油三酯小鼠的病理性骨吸收 TACE/FICD轴通过识别直接的 FICD的途径/靶点。我们预计，更好地了解TACE/c的不同角色- FMS/FICD通路将促进我们对破骨细胞生物学基础的理解，并针对 TACE/FICD轴可能为减轻炎性关节炎的骨吸收提供新的途径。

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.