Abstract
Cherubism (OMIM#118400) is a craniofacial disorder characterized by destructive jaw expansion. Gain-of-function mutations in SH3-domain binding protein 2 (SH3BP2) are responsible for this rare disorder. We have previously shown that homozygous knock-in (KI) mice (Sh3bp2 (KI/KI) ) recapitulate human cherubism by developing inflammatory lesions in the jaw. However, it remains unknown why heterozygous KI mice (Sh3bp2 (KI/+) ) do not recapitulate the excessive jawbone destruction in human cherubism, even though all mutations are heterozygous in humans. We hypothesized that Sh3bp2 (KI/+) mice need to be challenged for developing exacerbated jawbone destruction and that bacterial stimulation in the oral cavity may be involved in the mechanism. In this study, we applied a ligature-induced periodontitis model to Sh3bp2 (KI/+) mice to induce inflammatory alveolar bone destruction. Ligature placement induced alveolar bone resorption with gingival inflammation. Quantification of alveolar bone volume revealed that Sh3bp2 (KI/+) mice developed more severe bone loss (male: 43.0% ± 10.6%, female: 42.6% ± 10.4%) compared with Sh3bp2 (+/+) mice (male: 25.8% ± 4.0%, female: 30.9% ± 6.5%). Measurement of bone loss by the cement-enamel junction-alveolar bone crest distance showed no difference between Sh3bp2 (KI/+) and Sh3bp2 (+/+) mice. The number of osteoclasts on the alveolar bone surface was higher in male Sh3bp2 (KI/+) mice, but not in females, compared with Sh3bp2 (+/+) mice. In contrast, inflammatory cytokine levels in gingiva were comparable between Sh3bp2 (KI/+) and Sh3bp2 (+/+) mice with ligatures. Genetic deletion of the spleen tyrosine kinase in myeloid cells and antibiotic treatment suppressed alveolar bone loss in Sh3bp2 (KI/+) mice, suggesting that increased osteoclast differentiation and function mediated by SYK and accumulation of oral bacteria are responsible for the increased alveolar bone loss in Sh3bp2 (KI/+) mice with ligature-induced periodontitis. High amounts of oral bacterial load caused by insufficient oral hygiene could be a trigger for the initiation of jawbone destruction in human cherubism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.