Kuboi Yoshikazu, Kuroda Yukiko, Ohkuro Masayoshi, Motoi Sotaro, Tomimori Yoshiya, Yasuda Hisataka, Yasuda Nobuyuki, Imai Toshio, Matsuo Koichi
KAN Research Institute Inc. Kobe Japan.
Tsukuba Research Laboratories, Eisai Co. Ltd. Tsukuba Japan.
JBMR Plus. 2022 Sep 22;6(10):e10680. doi: 10.1002/jbm4.10680. eCollection 2022 Oct.
The chemokine fractalkine (FKN) is produced by various cell types, including osteoblasts and endothelial cells in bone tissue, and signals through a sole receptor, CX3CR1, which is expressed on monocytes/macrophages, including osteoclast precursors (OCPs). However, the direct effects of FKN signaling on osteoclast lineage cells under homeostatic noninflammatory conditions remain unclear. Here, we report that FKN regulates mouse OCP survival and primes OCPs for subsequent osteoclast differentiation. Wild-type but not CX3CR1-deficient OCPs grown on immobilized FKN showed enhanced osteoclast formation following receptor activator of NF-κB ligand (RANKL) stimulation, with increased expression of osteoclast differentiation markers. Interestingly, the growth of OCPs on immobilized FKN increased the expression of and () transcripts, but following RANKL stimulation, OCPs rapidly downregulated expression. Consistently, anti-FKN monoclonal antibody (mAb) treatment attenuated RANKL-induced osteoclast formation on immobilized FKN before, but not during, RANKL stimulation. CX3CR1 and RANK proteins were highly expressed on bone marrow-derived CD11b CD115 OCPs. Growth on immobilized FKN prior to RANKL stimulation also increased CD11b CD115 OCP number and their survival and differentiation potential. In a RANKL-based mouse model of bone loss, anti-FKN mAb pretreatment significantly inhibited RANKL-dependent bone loss. Thus, blocking the FKN-CX3CR1 axis could represent a therapeutic option in noninflammatory bone loss diseases. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
趋化因子 fractalkine（FKN）由多种细胞类型产生，包括骨组织中的成骨细胞和内皮细胞，并通过唯一的受体 CX3CR1 发出信号，CX3CR1 在单核细胞/巨噬细胞上表达，包括破骨细胞前体（OCPs）。然而，在稳态非炎症条件下，FKN 信号对破骨细胞谱系细胞的直接影响仍不清楚。在此，我们报告 FKN 调节小鼠 OCP 的存活，并使 OCP 为随后的破骨细胞分化做好准备。在固定化 FKN 上生长的野生型而非 CX3CR1 缺陷型 OCP，在核因子κB 受体激活剂配体（RANKL）刺激后，破骨细胞形成增强，破骨细胞分化标志物的表达增加。有趣的是，OCP 在固定化 FKN 上的生长增加了 和 （）转录本的表达，但在 RANKL 刺激后，OCP 迅速下调 表达。一致地，抗 FKN 单克隆抗体（mAb）处理在 RANKL 刺激之前而非期间减弱了固定化 FKN 上 RANKL 诱导的破骨细胞形成。CX3CR1 和 RANK 蛋白在骨髓来源的 CD11b CD115 OCP 上高表达。在 RANKL 刺激之前在固定化 FKN 上生长也增加了 CD11b CD115 OCP 的数量及其存活和分化潜能。在基于 RANKL 的小鼠骨质流失模型中，抗 FKN mAb 预处理显著抑制了 RANKL 依赖性骨质流失。因此，阻断 FKN-CX3CR1 轴可能代表非炎症性骨质流失疾病的一种治疗选择。© 2022 作者。由 Wiley Periodicals LLC 代表美国骨与矿物质研究协会出版。
