Yan Guangqi, Guo Yan, Guo Jingwen, Wang Qiang, Wang Chunyu, Wang Xue
Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, 110002, Liaoning, China.
Key Laboratory of Oral Disease Liaoning Province, Shenyang, 110002, Liaoning, China.
Inflammation. 2020 Aug;43(4):1279-1292. doi: 10.1007/s10753-020-01207-y.
Chronic inflammatory diseases affect bone and teeth health tremendously. Characterized by osteolytic lesion and hyperactive osteoclastogenesis, inflammatory bone diseases are short of effective therapeutics and therefore highlight the importance of understanding pathogenesis and developing ideal medications. Reactive oxygen species (ROS) play a prominent role in the innate immune response of activated macrophages, as well as in the physiological signaling of osteoclasts (OCs) differentiation. N-acetylcysteine (NAC) is a potent ROS scavenger and a potential option for treating diseases characterized by excessive ROS generation. However, whether NAC can protect physiological bone remodeling from in vivo inflammatory conditions is largely undefined. We applied NAC treatment on lipopolysaccharide (LPS)-induced inflammatory osteolysis mice model and found that NAC could attenuate bone erosion and protect mice against LPS-induced osteolysis, due to the suppressive effect on osteoclastogenesis and stimulated effect on osteogenesis. Moreover, in vitro study demonstrated that, in OC precursors (pre-OCs), LPS-stimulated expressions of OC marker genes, such as tartrate-resistant acid phosphatase type 5 (Acp5), cathepsin K (Ctsk), OC stimulatory transmembrane protein (Oc-stamp), dendritic cell-specific transmembrane protein (Dc-stamp), and nuclear factor of activated T cells 1 (NFATc1), were all reduced because of the NAC pretreatment, thereby adversely affecting OC function including F-actin ring formation and bone resorption. Further mechanism study showed that NAC blocked LPS-induced ROS formation in both macrophages and pre-OCs, cutting off the LPS-stimulated autocrine/paracrine mechanism during inflammatory osteolysis. Our findings reveal that NAC attenuates inflammatory osteolysis via the elimination of ROS formation during LPS-stimulated osteoclastogenesis, and provide a potential therapeutic approach to treat inflammatory bone disease.
慢性炎症性疾病对骨骼和牙齿健康有极大影响。炎症性骨病以溶骨性病变和破骨细胞生成亢进为特征，缺乏有效的治疗方法，因此凸显了理解发病机制和开发理想药物的重要性。活性氧（ROS）在活化巨噬细胞的固有免疫反应以及破骨细胞（OC）分化的生理信号传导中发挥着重要作用。N-乙酰半胱氨酸（NAC）是一种有效的ROS清除剂，是治疗以ROS生成过多为特征的疾病的潜在选择。然而，NAC是否能保护生理性骨重塑免受体内炎症条件的影响在很大程度上尚不清楚。我们对脂多糖（LPS）诱导的炎症性骨溶解小鼠模型应用NAC治疗，发现NAC可以减轻骨侵蚀并保护小鼠免受LPS诱导的骨溶解，这是由于其对破骨细胞生成的抑制作用和成骨的刺激作用。此外，体外研究表明，在OC前体细胞（pre-OCs）中，由于NAC预处理，LPS刺激的OC标志物基因如抗酒石酸酸性磷酸酶5（Acp5）、组织蛋白酶K（Ctsk）、OC刺激跨膜蛋白（Oc-stamp）、树突状细胞特异性跨膜蛋白（Dc-stamp）和活化T细胞核因子1（NFATc1）的表达均降低，从而对包括F-肌动蛋白环形成和骨吸收在内的OC功能产生不利影响。进一步的机制研究表明，NAC阻断了巨噬细胞和pre-OCs中LPS诱导的ROS形成，切断了炎症性骨溶解过程中LPS刺激的自分泌/旁分泌机制。我们的研究结果表明，NAC通过消除LPS刺激的破骨细胞生成过程中的ROS形成来减轻炎症性骨溶解，并为治疗炎症性骨病提供了一种潜在的治疗方法。
