Molecular control of bone development and inflammation by FBXO11

项目摘要 慢性炎症会扰乱骨骼新陈代谢，促进骨质流失。牙周炎和种植体周炎是 口腔最常见的炎症性骨病。在这样一个炎热的环境中，骨头 形成和骨吸收分离，导致炎症性骨损伤、牙齿脱落和种植体 失败了。在这项研究中，我们提出了一种新的F-box蛋白11(FBXO11)调节骨骼的机制 发展和发炎。FBXO11是一种与中耳炎相关的蛋白质编码基因。 此外，它还在广泛的生物过程中发挥作用，包括黑素细胞凋亡、细胞周期 调控、细胞迁移、B细胞分化和上皮性癌进展。然而，这一影响 FBXO11对骨骼发育和炎症的影响尚未确定。我们的初步研究是在 小鼠成骨细胞和基因组动物模型显示FBXO11是一个关键的信号分子 通过抑制Snail1/赖氨酸特异性脱甲基酶1(LSD1)调控成骨分化。 此外，我们还发现FBXO11/Snail1/LSD1信号轴是一个重要的机制 慢性炎症病例中潜在的炎症性骨丢失，如牙周炎和周围炎 种植炎。在我们提出的研究中确定的新机制将对分子的发展至关重要 预防牙周和种植体周围感染的骨丢失和促进骨再生的策略。三 具体目标将解决FBXO11调控骨中成骨分化的主要假设 发展和发炎。特异性Aim1将确定FBXO11是否是成骨所必需的 用FBXO11过表达和敲除的成骨细胞培养诱导分化和骨生长 骨移植实验和有条件的FBXO11基因敲除小鼠模型。具体目标2将决定是否 FBXO11/Snail1/LSD1调节轴参与多菌素的炎症性骨重建 牙周炎和种植体周围炎动物。具体目标3将决定我们是否可以将此FBXO11轴呈现为 治疗牙周炎和种植体周围炎的新目标，这些牙周炎和种植体周围炎是严重的健康和经济负担 世界各地。我们提出了两种创新的方法，通过基因工程FBXO11进行基因治疗 成骨细胞的转基因及特异性LSD1抑制剂反式-2-苯基环丙胺的局部干预 (2-PCPA)，FDA批准的一种抗抑郁药物，用于防止骨丢失和促进骨再生。 如果这项拟议的研究证实了我们的假设，即改变2-PCPA的用途来治疗炎症性骨病， 我们将考虑将2-PCPA用于治疗慢性牙周炎和种植体周围炎的应用推广到临床 学习。

Project Summary Chronic inflammation disrupts bone metabolism and promotes bone loss. Periodontitis and peri-implantitis are the most common inflammatory bone diseases in the oral cavity. In such an inflammatory environment, bone formation and bone resorption uncouple, leading to inflammatory bone damage, tooth loss, and dental implant failure. In this study, we propose a novel mechanism by which F-BOX Protein11 (FBXO11) regulates bone development and inflammation. FBXO11 is a protein-coding gene associated with otitis media. Additionally, it functions in a broad range of biological processes including melanocyte apoptosis, cell cycle regulation, cell migration, B-cell differentiation, and epithelial cancer progression. However, the effect of FBXO11 on bone development and inflammation has not been determined. Our preliminary studies in murine osteoblasts and genomic animal model showed that FBXO11 is a critical signaling molecule governing osteogenic differentiation by inhibiting Snail1/ lysine-specific demethylase 1 (LSD1). Furthermore, we found that the FBXO11/Snail1/LSD1 signaling axis is an important mechanism underlying inflammatory bone loss in cases of chronic inflammation, such as periodontitis and peri- implantitis. The novel mechanisms identified in our proposed studies will be critical for developing molecular strategies to prevent bone loss and promote bone regeneration in periodontal and peri-implant infection. Three specific aims will address the overarching hypothesis that FBXO11 regulates osteogenic differentiation in bone development and inflammation. Specific Aim1 will determine if FBXO11 is essential for osteogenic differentiation and bone growth by using FBXO11- overexpressing and knockdown osteogenic cells cultures, bone transplant experiment, and a conditional FBXO11 knockout mouse model. Specific Aim 2 will determine if FBXO11/Snail1/LSD1 regulatory axis contributes to inflammatory bone remodeling in the polymicrobial periodontitis and peri-implantitis animals. Specific Aim 3 will determine if we can render this FBXO11 axis as novel targets to treat periodontitis and peri-implantitis that represent significant health and economic burden world widely. We propose two innovative approaches, gene therapy by genetically engineering FBXO11 transgene in osteoblasts and a local intervention with a specific LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA), an FDA-approved antidepressant medication to prevent bone loss and promote bone regeneration. If this proposed study validates our hypothesis of repurposing of 2-PCPA to treat inflammatory bone disease, we will consider advancing the use of 2-PCPA to treat chronic periodontitis and peri-implantitis into clinical studies.