Tomoyuki Mukai1,2, Takahiko Akagi2, Sumie Hiramatsu Asano2, Ikue Tosa3, Mitsuaki Ono4, Mizuho Kittaka5,6, Yasuyoshi Ueki5,6, Ayano Yahagi1, Masanori Iseki1, Toshitaka Oohashi4, Katsuhiko Ishihara1, Yoshitaka Morita2. 1. Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Okayama, Japan. 2. Department of Rheumatology, Kawasaki Medical School, Kurashiki, Okayama, Japan. 3. Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan. 4. Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan. 5. Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, Indiana, USA. 6. Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Abstract
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.
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.
Authors: Y Ueki; V Tiziani; C Santanna; N Fukai; C Maulik; J Garfinkle; C Ninomiya; C doAmaral; H Peters; M Habal; L Rhee-Morris; J B Doss; S Kreiborg; B R Olsen; E Reichenberger Journal: Nat Genet Date: 2001-06 Impact factor: 38.330
Authors: Noam Levaot; Oleksandr Voytyuk; Ioannis Dimitriou; Fabrice Sircoulomb; Arun Chandrakumar; Marcel Deckert; Paul M Krzyzanowski; Andrew Scotter; Shengqing Gu; Salima Janmohamed; Feng Cong; Paul D Simoncic; Yasuyoshi Ueki; Jose La Rose; Robert Rottapel Journal: Cell Date: 2011-12-09 Impact factor: 41.582
Authors: M Hero; A Suomalainen; J Hagström; P Stoor; R Kontio; H Alapulli; S Arte; S Toiviainen-Salo; P Lahdenne; O Mäkitie Journal: Bone Date: 2012-10-12 Impact factor: 4.398
Authors: Ioannis D Dimitriou; Korris Lee; Itoro Akpan; Evan F Lind; Valarie A Barr; Pamela S Ohashi; Lawrence E Samelson; Robert Rottapel Journal: Cell Rep Date: 2018-07-31 Impact factor: 9.423