Browsing by Author "Ono, Mitsuaki"

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    Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model
    (Wiley, 2021) Mukai, Tomoyuki; Akagi, Takahiko; Hiramatsu Asano, Sumie; Tosa, Ikue; Ono, Mitsuaki; Kittaka, Mizuho; Ueki, Yasuyoshi; Yahagi, Ayano; Iseki, Masanori; Oohashi, Toshitaka; Ishihara, Katsuhiko; Morita, Yoshitaka; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Objective Cherubism is a genetic disorder characterised by bilateral jawbone deformation. The associated jawbone lesions regress after puberty, whereas severe cases require surgical treatment. Although several drugs have been tested, fundamental treatment strategies for cherubism have not been established. The effectiveness of imatinib has recently been reported; however, its pharmaceutical mechanism remains unclear. In this study, we tested the effects of imatinib using a cherubism mouse model. Methods We used Sh3bp2 P416R cherubism mutant mice, which exhibit systemic organ inflammation and osteopenia. The effects of imatinib were determined using primary bone marrow-derived macrophages. Imatinib was administered intraperitoneally to the mice, and serum tumour necrosis factor-α (TNFα), organ inflammation and bone properties were examined. Results The cherubism mutant macrophages produced higher levels of TNFα in response to lipopolysaccharide compared to wild-type macrophages, and imatinib did not significantly suppress TNFα production. Although imatinib suppressed osteoclast formation in vitro, administering it in vivo did not suppress organ inflammation and osteopenia. Conclusion The in vivo administration of imatinib had a minimal therapeutic impact in cherubism mutant mice. To establish better pharmaceutical interventions, it is necessary to integrate new findings from murine models with clinical data from patients with a definitive diagnosis of cherubism.
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    Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families
    (Oxford University Press, 2024-04-09) Kittaka, Mizuho; Mizuno, Noriyoshi; Morino, Hiroyuki; Yoshimoto, Tetsuya; Zhu, Tianli; Liu, Sheng; Wang, Ziyi; Mayahara, Kotoe; Iio, Kyohei; Kondo, Kaori; Kondo, Toshio; Hayashi, Tatsuhide; Coghlan, Sarah; Teno, Yayoi; Doan, Andrew Anh Phung; Levitan, Marcus; Choi, Roy B.; Matsuda, Shinji; Ouhara, Kazuhisa; Wan, Jun; Cassidy, Annelise M.; Pelletier, Stephane; Nampoothiri, Sheela; Urtizberea, Andoni J.; Robling, Alexander G.; Ono, Mitsuaki; Kawakami, Hideshi; Reichenberger, Ernst J.; Ueki, Yasuyoshi; Anatomy, Cell Biology and Physiology, School of Medicine
    Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders