CCL2 是牙周炎的关键调节因子和治疗靶点。

CCL2 is a key regulator and therapeutic target for periodontitis.

机构信息

Department of Periodontology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.

Department of Emergency, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.

出版信息

J Clin Periodontol. 2023 Dec;50(12):1644-1657. doi: 10.1111/jcpe.13872. Epub 2023 Sep 11.

DOI:10.1111/jcpe.13872

PMID:37697486

Abstract

AIM

Our previous study revealed that the C-C motif chemokine receptor 2 (CCR2) is a promising target for periodontitis prevention and treatment. However, CCR2 is a receptor with multiple C-C motif chemokine ligands (CCLs), including CCL2, CCL7, CCL8, CCL13 and CCL16, and which of these ligands plays a key role in periodontitis remains unclear. The aim of the present study was to explore the key functional ligand of CCR2 in periodontitis and to evaluate the potential of the functional ligand as a therapeutic target for periodontitis.

MATERIALS AND METHODS

The expression levels and clinical relevance of CCR2, CCL2, CCL7, CCL8, CCL13 and CCL16 were studied using human samples. The role of CCL2 in periodontitis was evaluated by using CCL2 knockout mice and overexpressing CCL2 in the periodontium. The effect of local administration of bindarit in periodontitis was evaluated by preventive and therapeutic medication in a mouse periodontitis model. Microcomputed tomography, haematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, bead-based immunoassays and flow cytometry were used for histomorphology, molecular biology and cytology analysis.

RESULTS

Among different ligands of CCR2, only CCL2 was significantly up-regulated in periodontitis gingival tissues and was positively correlated with the severity of periodontitis. Mice lacking CCL2 showed milder inflammation and less bone resorption than wild-type mice, which was accompanied by a reduction in monocyte/macrophage recruitment. Adeno-associated virus-2 vectors overexpressing CCL2 in Ccl2 mice gingiva reversed the attenuation of periodontitis in a CCR2-dependent manner. In ligation-induced experimental periodontitis, preventive or therapeutic administration of bindarit, a CCL2 synthesis inhibitor, significantly inhibited the production of CCL2, decreased the osteoclast number and bone loss and reduced the expression levels of proinflammatory cytokines TNF-α, IL-6 and IL-1β.

CONCLUSIONS

CCL2 is a pivotal chemokine that binds to CCR2 during the progression of periodontitis, and targeting CCL2 may be a feasible option for controlling periodontitis.

摘要

目的

我们之前的研究表明，C-C 基序趋化因子受体 2（CCR2）是预防和治疗牙周炎的有前途的靶点。然而，CCR2 是一种具有多种 C-C 基序趋化因子配体（CCLs）的受体，包括 CCL2、CCL7、CCL8、CCL13 和 CCL16，其中哪种配体在牙周炎中起关键作用尚不清楚。本研究旨在探讨 CCR2 在牙周炎中的关键功能配体，并评估该功能配体作为牙周炎治疗靶点的潜力。

材料和方法

使用人样本研究 CCR2、CCL2、CCL7、CCL8、CCL13 和 CCL16 的表达水平及其临床相关性。通过 CCL2 基因敲除小鼠和牙周组织中过表达 CCL2 来评估 CCL2 在牙周炎中的作用。通过在小鼠牙周炎模型中进行预防性和治疗性药物治疗，评估 bindarit 局部给药对牙周炎的影响。采用微计算机断层扫描、苏木精和伊红染色、抗酒石酸酸性磷酸酶染色、实时定量聚合酶链反应、酶联免疫吸附试验、珠基免疫分析和流式细胞术进行组织形态学、分子生物学和细胞学分析。

结果

在 CCR2 的不同配体中，只有 CCL2 在牙周炎牙龈组织中显著上调，且与牙周炎的严重程度呈正相关。缺乏 CCL2 的小鼠与野生型小鼠相比，炎症较轻，骨吸收较少，单核细胞/巨噬细胞募集减少。AAV-2 载体过表达 Ccl2 小鼠牙龈中的 CCL2 以 CCR2 依赖性方式逆转了牙周炎的减弱。在结扎诱导的实验性牙周炎中，预防性或治疗性给予 CCL2 合成抑制剂 bindarit 可显著抑制 CCL2 的产生，减少破骨细胞数量和骨丢失，并降低促炎细胞因子 TNF-α、IL-6 和 IL-1β的表达水平。