title: Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism.
abstract: Cherubism is caused by mutations in SH3BP2. Studies of cherubism mice showed that tumor necrosis factor α (TNF-α)-dependent autoinflammation is a major cause of the disorder but failed to explain why human cherubism lesions are restricted to jaws and regress after puberty. We demonstrate that the inflammation in cherubism mice is MYD88 dependent and is rescued in the absence of TLR2 and TLR4. However, germ-free cherubism mice also develop inflammation. Mutant macrophages are hyperresponsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) that activate Toll-like receptors (TLRs), resulting in TNF-α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-α production. Finally, SYK depletion in macrophages prevents the inflammation. These data suggest that the presence of a large amount of TLR ligands, presumably oral bacteria and DAMPs during jawbone remodeling, may cause the jaw-specific development of human cherubism lesions. Reduced levels of DAMPs after stabilization of jaw remodeling may contribute to the age-dependent regression.
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yoshitaka
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mukai
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Kittaka
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Alford
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Salome
authors.initials: S
authors.lastname: Masrani
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA; Division of Applied Life Science, Department of Periodontal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Ishida
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA; Division of Applied Life Science, Department of Periodontal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Mizuno
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
authors.affiliation: Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Reichenberger
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Electronic address: uekiy@umkc.edu.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ueki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002636:Cherubism / Q000209:etiology*; D004195:Disease Models, Animal; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007568:Jaw / Q000000981:diagnostic imaging; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011859:Radiography; D015398:Signal Transduction; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000737:chemistry / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; C484644:Sh3bp2 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse