Abstract
ABSTRACTCherubism (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.
Highlights
Cherubism (OMIM#118400) is an autosomal-dominant craniofacial disorder in children characterized by expansive destruction of the maxilla and mandible
We discovered that heterozygous gain-of-function mutations in the signaling adaptor protein SH3-domain binding protein 2 (SH3BP2) cause cherubism.(1) We have shown that homozygous knock-in (KI) mice (Sh3bp2KI/KI) harboring the most common mutation in cherubism patients recapitulate the many features of human cherubism by developing spontaneous fibrous inflammatory lesions and by exhibiting increased osteoclast formation in the jaw.(2) Homozygous mutant macrophages exhibit hyper-responsiveness against bacterial pathogens via Toll-like receptors (TLRs), and heterozygous and homozygous cherubism mutations promote osteoclastogenesis induced by RANKL and TNF-ɑ.(2–4) The mode of inheritance of cherubism lesion development is different between humans and mice
A few tartrateresistant acid phosphatase (TRAP)-positive multinucleated cells were observed within connective tissues underneath the ligated second molar in Sh3bp2+/+ and Sh3bp2KI/+ mice (Fig. 1B). qPCR analysis of gingival tissue showed that expression levels of Adgre and Itgam, Ly6g, Cxcr[2], Cxcr[4], and Cd3g were not significantly changed between ligated Sh3bp2+/+ and Sh3bp2KI/+ mice (Supplemental Fig. S1)
Summary
Cherubism (OMIM#118400) is an autosomal-dominant craniofacial disorder in children characterized by expansive destruction of the maxilla and mandible. 1 of 9 n develop as an autosomal dominant trait, whereas heterozygosity of the SH3BP2 gain-of-function mutation is not sufficient to develop spontaneous cherubism lesions in our mouse model.(2) As a result, most studies in the cherubism mouse model have been conducted in homozygous Sh3bp2KI/KI mice, where they express stronger phenotypes than human cherubism. It remains unknown why heterozygous KI mice (Sh3bp2KI/+) do not recapitulate the destructive jawbone phenotype in human cherubism. Oral microbe-dependent alveolar bone loss in Sh3bp2KI/+ mice suggests that a high oral bacterial load, for example, caused by insufficient oral hygiene, could be a trigger of jawbone destruction in human cherubism and that reduction of bacterial load by increased oral hygiene could reduce the risk of severe jawbone destruction in cherubism patients
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