Proteasomal regulation of TNF-mediated local bone loss

TNF介导的局部骨质流失的蛋白酶体调节

• 批准号: 7197380
• 负责人: LIANPING XING
• 金额: $ 15.4万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-26 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197380
• 关键词: bone; osteoblasts

DESCRIPTION (provided by applicant): Chronic inflammatory bone diseases, such as rheumatoid arthritis, are characterized by local bone loss that is largely due to the effects of increased production of pro-inflammatory cytokines, IL-1, IL-6, and TNF. These cytokines cause enhanced osteoclastogenesis, and reduced osteoblast activity and survival. Although much is known about how cytokines stimulate focal osteoclastic bone erosion, the mechanisms by which cytokines inhibit osteoblast function remain unclear. In the past several years, the E3 ubiquitin ligase, Smad ubiquitin regulatory factor (Smurf1), has been reported to promote degradation of the osteoblast- specific transcription factor, Runx2, thereby inhibiting osteoblast differentiation. However, the regulation of Smurf and its role in the pathogenesis of inflammation-induced local bone loss have not been investigated. Recently, we have demonstrated that TNF stimulates Smurf1 expression in osteoblasts, which result in Runx2 degradation. TNF-mediated Runx2 degradation is associated with increased ubiquitination, which can be blocked by inhibitory RNA to Smurfl and proteasomal inhibitors. Consistent with this, tissues from joints of rheumatoid arthritic patients and TNF transgenic arthritic mice have high levels of Smurf1 and TNF expression. Based on these preliminary findings, we hypothesize that under inflammatory conditions, TNF or/and other cytokines inhibit osteoblast function through the up-regulation of Smurf-proteasomal degradation pathway. Here we propose to determine the effect of TNF on the Smurf pathway in osteoblasts in vitro, and the effect of Smurf1 deficiency on TNF-mediated osteoblast inhibition in vivo using TNF transgenic and Smurf1-/- mice. The overall purpose of this application is to validate the significance of the Smurf-proteasomal pathway in cytokine-mediated local bone loss. Results from this study should open up a new field of investigation into the involvement of Smurf E3 ligases in inflammation-mediated osteoblast inhibition in erosive bone diseases.

描述（由申请人提供）：慢性炎性骨疾病，如类风湿性关节炎，其特征在于局部骨丢失，这主要是由于促炎细胞因子IL-1、IL-6和TNF产生增加的影响。这些细胞因子导致破骨细胞生成增强，成骨细胞活性和存活减少。尽管人们对细胞因子如何刺激局灶性破骨细胞性骨侵蚀已有很多了解，但细胞因子抑制成骨细胞功能的机制仍不清楚。在过去的几年中，E3泛素连接酶，Smad泛素调节因子（Smurf 1），已被报道促进成骨细胞特异性转录因子Runx 2的降解，从而抑制成骨细胞分化。然而，Smurf的调节及其在炎症诱导的局部骨丢失的发病机制中的作用尚未研究。最近，我们已经证明，TNF刺激Smurf 1在成骨细胞中的表达，导致Runx 2降解。TNF介导的Runx 2降解与增加的泛素化相关，这可以被Smurfl的抑制性RNA和蛋白酶体抑制剂阻断。与此一致，类风湿性关节炎患者和TNF转基因关节炎小鼠的关节组织具有高水平的Smurf 1和TNF表达。基于这些初步发现，我们推测在炎症条件下，TNF或/和其他细胞因子通过上调Smurf-蛋白酶体降解途径抑制成骨细胞功能。在这里，我们建议，以确定在体外成骨细胞的Smurf通路的TNF的影响，和在体内使用TNF转基因和Smurf 1-/-小鼠的Smurf 1缺陷对TNF介导的成骨细胞抑制的影响。本申请的总体目的是验证Smurf-蛋白酶体途径在苦参碱介导的局部骨丢失中的意义。这项研究的结果应该开辟了一个新的领域的调查参与Smurf E3连接酶炎症介导的成骨细胞抑制侵蚀性骨疾病。