CCL2 is a key regulator and therapeutic target for periodontitis.

Abstract

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 chemokineligands (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. 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. 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 gingivareversed 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. 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.