Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates excessive bone loss and osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway.
Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates excessive bone loss and osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway.
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心肌营养素样细胞因子因子 1 (CLCF1) 通过激活干扰素信号传导和抑制核因子-κB 信号传导通路来缓解过度骨质流失和破骨细胞分化。
DOI：
10.1016/j.bone.2021.116140
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发表时间：
2021
期刊：
影响因子：
4.1
通讯作者：
Norimasa Iwasaki
中科院分区：
文献类型：
--
作者：
Shunichi Yokota;Gen Matsumae;Tomohiro Shimizu;Tomoka Hasegawa;Taku Ebata;Daisuke Takahashi;Cai Heguo;Yuan Tian;Hend Alhasan;Masahiko Takahata;Ken Kadoya;Alaa Terkawi;Norimasa Iwasaki
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希望的治疗药物。CLCF1是一种免疫细胞来源的分子，据报道，在绝经后骨质疏松症患者中，CLCF1的表达降低。这表明它可能与骨重塑有关。因此，我们探讨了CLCF1在骨质疏松症相关的破骨细胞发生和骨质流失中的功能作用。令人惊讶的是，重组CLCF1抑制了卵巢切除小鼠的过度骨质流失，并阻止了颅骨小鼠模型中rankl诱导的骨质流失。同样，将重组CLCF1添加到rankl刺激的单核细胞中，可以在体外观察到牙本质切片上具有小吸收面积的分化破骨细胞的数量明显受到抑制。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治疗对破骨细胞分化的抑制似乎与干扰素信号通路（IFN）的激活和NF-κB信号通路的抑制有关。有趣的是，早在CLCF1刺激后1小时，巨噬细胞中就检测到ifn信号的主要成分STAT1和IRF1的表达。与这些结果一致的是，在体外巨噬细胞中阻断STAT1可以消除CLCF1对破骨细胞分化的抑制作用。这些共同的发现指出了CLCF1在骨重塑中的一种新的免疫调节功能，并强调了它作为治疗骨质疏松症的潜在有用的治疗剂。
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.