Kittaka Mizuho, Yoshimoto Tetsuya, Hoffman Henry, Levitan Marcus Evan, Ueki Yasuyoshi
Department of Biomedical Sciences and Comprehensive Care, Indiana University, School of Dentistry, Indianapolis, IN 46202, USA.
Indiana Center for Musculoskeletal Health, Indiana University, School of Medicine, Indianapolis, IN 46202, USA.
Bone Rep. 2020 Mar 27;12:100258. doi: 10.1016/j.bonr.2020.100258. eCollection 2020 Jun.
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 RANKL/RANK-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 RANKL/RANK in NF-κB2- and RBP-J-deficient mice, suggesting that inflammatory challenges and secondary gene manipulation are the prerequisites for RANKL/RANK-deficient mice to develop osteoclasts . Here we report that, even in the absence of RANKL ( ), cherubism mice ( ) harboring the homozygous gain-of-function mutation in SH3-domain binding protein 2 (SH3BP2) develop tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts spontaneously. The mice exhibit an increase in tooth exposure and a decrease in bone volume/total volume compared to mice. The multinucleated cells were stained positively for cathepsin K. Osteoclastic marker gene expression in bone and serum TRAP5b levels were elevated in mice. Elevation of the serum TNF-ɑ levels suggested that TNF-ɑ is a driver for the RANKL-independent osteoclast formation in mice. 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.
尽管核因子-κB 配体（RANKL）的受体激活剂及其受体 RANK 在破骨细胞生成中具有独特作用，但不依赖 RANKL/RANK 的破骨细胞生成的可能性在骨生物学领域一直是长期争论的话题。相比之下，有报道称，在 NF-κB2 和 RBP-J 缺陷小鼠中，颅骨注射 TNF-α 在没有 RANKL/RANK 的情况下会引发显著的破骨细胞生成，这表明炎症刺激和二次基因操作是 RANKL/RANK 缺陷小鼠发育出破骨细胞的先决条件。在此我们报告，即使在没有 RANKL 的情况下，携带 SH3 结构域结合蛋白 2（SH3BP2）纯合功能获得性突变的 cherubism 小鼠会自发地产生抗酒石酸酸性磷酸酶（TRAP）阳性的多核破骨细胞。与野生型小鼠相比，cherubism 小鼠的牙齿暴露增加，骨体积/总体积减少。多核细胞组织蛋白酶 K 染色呈阳性。cherubism 小鼠骨骼中的破骨细胞标记基因表达和血清 TRAP5b 水平升高。血清 TNF-α 水平升高表明 TNF-α 是 cherubism 小鼠中不依赖 RANKL 的破骨细胞形成的驱动因素。我们的研究结果提供了一种新的突变模型，该模型可在不依赖 RANKL 的情况下发育出破骨细胞，并证实 SH3BP2 的功能获得不仅在有 RANKL 存在时促进破骨细胞生成，而且在没有 RANKL 时也能促进破骨细胞生成。
