Nucleosides and TREM2 Mediate Inflammation-Induced Bone Loss

描述（由申请人提供）： 炎症诱导的骨质溶解，如发生在类风湿性关节炎和银屑病关节炎，是最常见的骨骼疾病之一。以往的研究大多集中在炎症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，中断细胞因子不能完全阻止骨侵蚀，这意味着存在其他骨吸收的关键途径。在这项提案中，我们将从一个完全不同的角度研究炎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，TREM2因此是连接炎症，免疫功能和骨代谢的独特受体。我们先前的研究表明，TREM2途径也与抗病毒核苷类似物诱导的破骨细胞生成升高相关。TREM2已被证明是一种共刺激受体，可增强RANK介导的破骨细胞生成。然而，TREM2的特异性配体尚未鉴定。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起来。类风湿性关节炎（RA）患者的滑液中积累了丰富的核苷。因此，我们的假设是，炎症引起的骨破坏是通过积聚的核苷激活TREM 2途径介导的，该途径增强了RANK依赖性破骨细胞生成。这一建议将阐明炎症性骨丢失的发病机制在分子水平上。有两个具体目标：具体目标I在体内和体外表征核苷类药物的破骨细胞生成作用。部分A.表征核苷在小鼠中的破骨细胞生成作用。B部分。在体外和体内表征阻断TREM2的抗溶骨性作用。具体目的II描述TREM2通路在核苷增强的破骨细胞生成中的作用。部分A.表征核苷与TREM2受体的结合。部分B。确定核苷对TREM2表达的影响。部分C.确定由核苷刺激的TREM2途径中的细胞内信号。炎症引起的骨质溶解，如发生在类风湿性关节炎和银屑病关节炎，是最常见的骨骼疾病之一。本研究拟探讨炎症病原体或受损宿主细胞释放的大量核苷在炎症性骨破坏中的致病作用及其分子机制。这些研究将为炎症引起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.