RANKL-independent osteoclastogenesis in the SH3BP2 cherubism mice.
RANKL-independent osteoclastogenesis in the SH3BP2 cherubism mice.
复制标题
SH3BP2 天使小鼠中 RANKL 独立的破骨细胞生成。
DOI：
10.1016/j.bonr.2020.100258
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发表时间：
2020
期刊：
影响因子：
2.5
通讯作者：
Ueki,Yasuyoshi
中科院分区：
文献类型：
--
作者：
Kittaka,Mizuho;Yoshimoto,Tetsuya;Hoffman,Henry;Levitan,MarcusEvan;Ueki,Yasuyoshi
尽管核因子受体激活物-κB配体(RANKL)及其受体RANK在破骨细胞生成中具有排他性作用，但RANK/RANKL非依赖性破骨细胞生成的可能性一直是骨生物学争论的主题。相反，有报道称，在缺乏RANK/RANKL的情况下，颅骨注射肿瘤坏死因子-ɑ可在缺乏RANK/κB2和RBP-J的小鼠中诱导显著的破骨细胞生成，提示炎症挑战和二次基因操作是RANK/RANKL缺陷小鼠在体内形成破骨细胞的先决条件。在这里，我们报道，即使在没有RANKL(RANKL−/−)的情况下，携带SH3BP2纯合子功能获得突变的小鼠(Sh3bp2KI/Ki)也会自发地发展出酒石酸抗性酸性磷酸酶(TRAP)阳性的多核破骨细胞。Sh3bp2KI/KIRank1−/−小鼠与Sh3bp2+/+RANKL−/−小鼠相比，牙齿暴露增加，骨体积/总体积减少。Sh3bp2KI/KIRank1−/−小鼠多核细胞组织蛋白酶K染色阳性，破骨细胞标志物基因表达增加，血清TRAP5b水平升高。血清肿瘤坏死因子-ɑ水平的升高提示，肿瘤坏死因子-ɑ是Sh3bp2KI/K小鼠破骨细胞非依赖RANKL形成的驱动力。我们的结果提供了一种新的突变模型，该模型可以发展不依赖RANKL的破骨细胞，并证实SH3BP2的功能增强不仅在RANKL存在的情况下促进破骨细胞的生成，而且在RANKL缺乏的情况下也促进破骨细胞的生成。
Even though the receptor activator of the nuclear factor-κB ligand (RANKL) and its receptor RANK have an exclusive role in osteoclastogenesis, the possibility of RANK/RANKL-independent osteoclastogenesis has been the subject of a long-standing debate in bone biology. In contrast, it has been reported that calvarial injection of TNF-ɑ elicits significant osteoclastogenesis in the absence of RANK/RANKL in NF-κB2- and RBP-J-deficient mice, suggesting that inflammatory challenges and secondary gene manipulation are the prerequisites for RANK/RANKL-deficient mice to develop osteoclastsin vivo. Here we report that, even in the absence of RANKL (Rankl−/−), cherubism mice (Sh3bp2KI/KI) harboring the homozygous gain-of-function mutation in SH3-domain binding protein 2 (SH3BP2) develop tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts spontaneously. TheSh3bp2KI/KIRankl−/−mice exhibit an increase in tooth exposure and a decrease in bone volume/total volume compared toSh3bp2+/+Rankl−/−mice. The multinucleated cells were stained positively for cathepsin K. Osteoclastic marker gene expression in bone and serum TRAP5b levels were elevated inSh3bp2KI/KIRankl−/−mice. Elevation of the serum TNF-ɑ levels suggested that TNF-ɑ is a driver for the RANKL-independent osteoclast formation inSh3bp2KI/KImice. Our results provide a novel mutant model that develops osteoclasts independent of RANKL and establish that the gain-of-function of SH3BP2 promotes osteoclastogenesis not only in the presence of RANKL but also in the absence of RANKL.