Macrophage colony-stimulating factor (M-CSF) and interleukin-34 (IL-34) are ligands for the colony-stimulating factor-1 receptor (CSF-1r) expressed on the surface of monocyte/macrophage lineage cells. The importance of coordinated signaling between M-CSF/receptor activator of the nuclear factor kappa-Β ligand (RANKL) in physiological and pathological bone remodeling and alveolar bone loss in response to oral bacterial colonization is well established. However, our knowledge about the IL-34/RANKL signaling in periodontal bone loss remains limited. Recently published cohort studies have demonstrated that the expression patterns of IL-34 are dramatically elevated in gingival crevicular fluid collected from patients with periodontitis. Therefore, the present study aims to evaluate the effects of IL-34 on osteoclastogenesis in vitro and in experimental ligature-mediated model of periodontitis using male mice. Our initial in vitro study demonstrated increased RANKL-induced osteoclastogenesis of IL-34-primed osteoclast precursors (OCPs) compared to M-CSF-primed OCPs. Using an experimental model of ligature-mediated periodontitis, we further demonstrated elevated expression of IL-34 in periodontal lesions. In contrast, M-CSF levels were dramatically reduced in these periodontal lesions. Furthermore, local injections of mouse recombinant IL-34 protein significantly elevated cathepsin K activity, increased the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and promoted alveolar bone loss in periodontitis lesions. In contrast, anti-IL-34 neutralizing monoclonal antibody significantly reduced the level of alveolar bone loss and the number of TRAP-positive osteoclasts in periodontitis lesions. No beneficial effects of locally injected anti-M-CSF neutralizing antibody were observed in periodontal lesions. This study illustrates the role of IL-34 in promoting alveolar bone loss in periodontal lesions and proposes the potential of anti-IL34 monoclonal antibody (mAb)-based therapeutic regimens to suppress alveolar bone loss in periodontitis lesions.

中文翻译：

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IL-34 和抗 IL-34 中和单克隆抗体对结扎诱导的牙周炎模型中牙槽骨丢失的影响

巨噬细胞集落刺激因子 (M-CSF) 和白细胞介素 34 (IL-34) 是单核细胞/巨噬细胞谱系细胞表面表达的集落刺激因子 1 受体 (CSF-1r) 的配体。M-CSF/核因子 kappa-B 配体受体激活剂 (RANKL) 之间协调信号传导在生理和病理性骨重塑以及口腔细菌定植引起的牙槽骨丢失中的重要性已得到充分证实。然而，我们对牙周骨丢失中 IL-34/RANKL 信号传导的了解仍然有限。最近发表的队列研究表明，从牙周炎患者收集的龈沟液中 IL-34 的表达模式显着升高。因此，本研究旨在评估 IL-34 对体外破骨细胞生成的影响以及使用雄性小鼠的实验性结扎介导的牙周炎模型。我们最初的体外研究表明，与 M-CSF 引发的破骨细胞前体 (OCP) 相比，RANKL 诱导的 IL-34 引发的破骨细胞前体 (OCP) 的破骨细胞生成增加。使用结扎介导的牙周炎实验模型，我们进一步证明了牙周病变中 IL-34 的表达升高。相比之下，这些牙周病变中的 M-CSF 水平显着降低。此外，局部注射小鼠重组IL-34蛋白可显着提高组织蛋白酶K活性，增加抗酒石酸酸性磷酸酶（TRAP）阳性破骨细胞的数量，并促进牙周炎病变中的牙槽骨丢失。相反，抗IL-34中和单克隆抗体显着降低牙周炎病变中牙槽骨丢失的水平和TRAP阳性破骨细胞的数量。在牙周病变中没有观察到局部注射抗 M-CSF 中和抗体的有益作用。这项研究阐明了 IL-34 在促进牙周病灶中牙槽骨流失中的作用，并提出了基于抗 IL34 单克隆抗体 (mAb) 的治疗方案抑制牙周炎病灶中牙槽骨流失的潜力。