Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
J Bone Miner Res. 2011 Aug;26(8):1913-25. doi: 10.1002/jbmr.400.
The innate immune system and its components play an important role in the pathogenesis of inflammatory bone destruction. Blockade of inflammatory cytokines does not completely arrest bone erosion, suggesting that other mediators also may be involved in osteolysis. Previously we showed that nucleosides promote osteoclastogenesis and bone-resorption activity in the presence of receptor activator for nuclear factor κB ligand (RANKL) in vitro. The studies described here further demonstrate that selected nucleosides and nucleoside analogues accelerate bone destruction in mice immunized with collagen II alone (CII) but also further enhance bone erosion in mice immunized by collagen II plus complete Freund's adjuvant (CII + CFA). Abundant osteoclasts are accumulated in destructive joints. These data indicate that nucleosides act as innate immune activators distinct from CFA, synergistically accelerating osteoclast formation and inflammatory osteolysis. The potential roles of the surface triggering receptor expressed on myeloid cells (TREM) and the intracellular inflammasome in nucleoside-enhanced osteoclastogenesis have been studied. These observations provide new insight into the pathogenesis and underlying mechanism of bone destruction in inflammatory autoimmune osteoarthritis.
固有免疫系统及其成分在炎症性骨破坏的发病机制中发挥重要作用。阻断炎症细胞因子并不能完全阻止骨质侵蚀，这表明其他介质也可能参与骨溶解。我们之前的研究表明，核苷在核因子 κB 配体（RANKL）存在的情况下促进体外破骨细胞生成和骨吸收活性。本文进一步研究表明，在单独用 II 型胶原（CII）免疫的小鼠中，选择的核苷和核苷类似物加速骨破坏，但在 CII 加完全弗氏佐剂（CII + CFA）免疫的小鼠中进一步增强骨侵蚀。在破坏性关节中积累了大量的破骨细胞。这些数据表明，核苷作为固有免疫激活剂，与 CFA 不同，协同加速破骨细胞形成和炎症性骨溶解。髓样细胞表面触发受体表达（TREM）和细胞内炎症小体在核苷增强破骨细胞生成中的潜在作用已被研究。这些观察结果为炎症性自身免疫性骨关节炎中骨破坏的发病机制和潜在机制提供了新的见解。
