Kittaka, MizuhoYoshimoto, TetsuyaHoffman, HenryLevitan, Marcus EvanUeki, Yasuyoshi2020-06-102020-06-102020-03-27Kittaka, M., Yoshimoto, T., Hoffman, H., Levitan, M. E., & Ueki, Y. (2020). RANKL-independent osteoclastogenesis in the SH3BP2 cherubism mice. Bone reports, 12, 100258. https://doi.org/10.1016/j.bonr.2020.100258https://hdl.handle.net/1805/22926Even 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 in 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. The Sh3bp2KI/KIRankl−/− mice exhibit an increase in tooth exposure and a decrease in bone volume/total volume compared to Sh3bp2+/+Rankl−/− mice. The multinucleated cells were stained positively for cathepsin K. Osteoclastic marker gene expression in bone and serum TRAP5b levels were elevated in Sh3bp2KI/KIRankl−/− mice. Elevation of the serum TNF-ɑ levels suggested that TNF-ɑ is a driver for the RANKL-independent osteoclast formation in Sh3bp2KI/KI 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalRANKL-independent osteoclastogenesisRANKLSH3BP2CherubismTNF-ɑArticle