Nucleosides and TREM2 Mediate Inflammation-Induced Bone Loss

描述(由申请人提供)： 炎症诱导的骨溶解是最常见的骨骼疾病之一，如类风湿性和银屑病关节炎。以往的研究大多集中在炎性或免疫细胞因子在炎性骨溶解发病机制中的作用。不幸的是，阻断细胞因子并不能完全阻止骨侵蚀，这意味着存在其他关键的骨吸收途径。在这个方案中，我们将从一个完全不同的角度来研究炎症性骨丢失的发病机制：炎症诱导的细胞外核苷作为髓样细胞上表达的触发受体2(TREM2)的配体，从而成为连接炎症、免疫功能和骨代谢的独特受体。我们以前的研究表明，TREM2通路也与抗病毒核苷类似物诱导的破骨细胞生成增加有关。TREM2已被证明是促进RANK介导的破骨细胞生成的共刺激受体。然而，TREM2的特异性配体尚未确定。我们假设核苷可能是TREM2受体的内源性配体，因为核苷可能将炎症、免疫系统和骨代谢联系在一起。类风湿性关节炎(RA)患者的滑液中积聚了丰富的核苷。因此，我们的假设是，炎症引起的骨破坏是通过累积的核苷激活TREM2途径来介导的，该途径促进了等级依赖的破骨细胞的形成。这一建议将从分子水平阐明炎症性骨丢失的发病机制。有两个特定的目的：特定的目的I表征核苷在体内和体外的破骨细胞生成作用。A部分核苷在小鼠体内的破骨细胞形成作用。第二部分研究封闭TREM2的体内外抗骨溶解作用。特定目的II表征TREM2通路在核苷促进破骨细胞生成中的作用。A部分描述核苷与TREM2受体的结合。B部分确定核苷对TREM2表达的影响。C部分确定核苷刺激的TREM2通路中的细胞内信号。项目简介炎症引起的骨溶解，如类风湿性和牛皮癣关节炎，是最常见的骨骼疾病之一。本研究将探讨炎症病原体或受损宿主细胞释放的大量核苷在炎症诱导的骨破坏中的致病作用和分子机制。这些研究将为炎症诱导的骨关节破坏提供新的治疗靶点。

DESCRIPTION (provided by applicant): Inflammation-induced osteolysis, such as occurs in rheumatoid and psoriatic arthritis, is one of the most common skeletal diseases. Most previous studies focused on the role of inflammatory or immune cytokines on pathogenesis of inflammatory osteolysis. Unfortunately, interrupting cytokines does not completely arrest the bone erosion implying the existence of other critical pathways for bone resorption. In this proposal, we will investigate the pathogenesis of inflammatory bone loss from a totally different angle: inflammation-induced extracellular nucleosides as ligands for the triggering receptor expressed on myeloid cells 2 (TREM2), which is thus a unique receptor linking inflammation, immune function and bone metabolism. Our previous studies demonstrated that the TREM2 pathway is also associated with elevated osteoclastogenesis induced by antiviral nucleoside analogs. TREM2 has been demonstrated to be a costimulatory receptor enhancing RANK-mediated osteoclastogenesis. However, the specific ligand for TREM2 has not yet been identified. We hypothesize that nucleosides may be an endogenous ligand for the TREM2 receptor, because nucleosides potentially link inflammation, immune system and bone metabolism. An abundance of nucleosides is accumulated in the synovial fluid of rheumatoid arthritis (RA) patients. Therefore, our hypothesis is that bone destruction caused by inflammation is mediated through accumulated nucleosides activating the TREM2 pathway that enhances the RANK-dependent osteoclastogenesis. This proposal will elucidate the pathogenesis of inflammatory bone loss at the molecular level. There are two specific aims: Specific Aim I Characterize the osteoclastogenic effects of nucleosides in vivo and in vitro. Part A. Characterize osteoclastogenic effects of nucleosides in mice. Part B. Characterize the anti-osteolytic effect of blocking TREM2 in vitro and in vivo. Specific Aim II Characterize the role of the TREM2 pathway in nucleoside enhanced osteoclastogenesis. Part A. Characterize the binding of nucleosides to the TREM2 receptor. Part B. Determine the effect of nucleosides on the expression of TREM2. Part C. Determine the intracellular signals in the TREM2 pathway stimulated by nucleosides. PROJECT NARRATIVE Inflammation-induced osteolysis, such as occurs in rheumatoid and psoriatic arthritis, is one of the most common skeletal diseases. This proposal will investigate the pathogenic role and molecular mechanism of abundant nucleosides released from inflammatory pathogens or damaged host cells in inflammation-induced bone destruction. These studies will provide a new therapeutic target for inflammation-induced bone-joint destruction.