Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo, 060-8638, Japan.
Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nish-7, Kita-ku, Sapporo, 060-8638, Japan.
Bone. 2021 Dec;153:116140. doi: 10.1016/j.bone.2021.116140. Epub 2021 Aug 5.
A growing body of evidence suggests that immune factors that regulate osteoclast differentiation and bone resorption might be promising therapeutic agents for the treatment of osteoporosis. The expression of CLCF1, an immune cell-derived molecule, has been reported to be reduced in patients with postmenopausal osteoporosis. This suggests that it may be involved in bone remodeling. Thus, we explored the functional role of CLCF1 in osteoclastogenesis and bone loss associated with osteoporosis. Surprisingly, the administration of recombinant CLCF1 repressed excessive bone loss in ovariectomized mice and prevented RANKL-induced bone loss in calvarial mouse model. Likewise, the addition of recombinant CLCF1 to RANKL-stimulated monocytes resulted in a significant suppression in the number of differentiated osteoclasts with small resorption areas being observed on dentine slices in vitro. At the same dosage, CLCF1 did not exhibit any detectable negative effects on the differentiation of osteoblasts. Mechanistically, the inhibition of osteoclast differentiation by the CLCF1 treatment appears to be related to the activation of interferon signaling (IFN) and the suppression of the NF-κB signaling pathway. Interestingly, the expression of the main components of IFN-signaling namely, STAT1 and IRF1, was detected in macrophages as early as 1 h after stimulation with CLCF1. Consistent with these results, the blockade of STAT1 in macrophages abolished the inhibitory effect of CLCF1 on osteoclast differentiation in vitro. These collective findings point to a novel immunoregulatory function of CLCF1 in bone remodeling and highlight it as a potentially useful therapeutic agent for the treatment of osteoporosis.
越来越多的证据表明，调节破骨细胞分化和骨吸收的免疫因子可能是治疗骨质疏松症的有前途的治疗剂。据报道，免疫细胞衍生分子 CLCF1 的表达在绝经后骨质疏松症患者中降低。这表明它可能参与骨重塑。因此，我们探讨了 CLCF1 在与骨质疏松症相关的破骨细胞生成和骨丢失中的功能作用。令人惊讶的是，重组 CLCF1 的给药抑制了去卵巢小鼠的过度骨丢失，并防止了 RANKL 诱导的颅骨小鼠模型中的骨丢失。同样，将重组 CLCF1 添加到 RANKL 刺激的单核细胞中导致体外牙本质切片上观察到分化的破骨细胞数量显着减少，且具有小的吸收面积。在相同剂量下，CLCF1 对成骨细胞的分化没有任何可检测到的负面影响。从机制上讲，CLCF1 处理对破骨细胞分化的抑制似乎与干扰素信号 (IFN) 的激活和 NF-κB 信号通路的抑制有关。有趣的是，早在用 CLCF1 刺激 1 小时后，就可以在巨噬细胞中检测到 IFN 信号的主要成分，即 STAT1 和 IRF1 的表达。与这些结果一致，在巨噬细胞中阻断 STAT1 消除了 CLCF1 对体外破骨细胞分化的抑制作用。这些综合结果表明 CLCF1 在骨重塑中具有新的免疫调节功能，并强调其作为治疗骨质疏松症的潜在有用治疗剂。
