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CBM mutation in Sh3bp2 enhances neutrophil‐mediated events that contribute to PAMPs‐induced jawbone expansion. (A) Increased SH3BP2 expression in sorted Ly6G‐positive cells from Sh3bp2KI/KI bone marrow shown by immunoblotting. (B) Increased percentages of blood neutrophils (Ly6G⁺CD115⁻) and monocytes (Ly6G⁻CD115⁺) in Sh3bp2KI/KI mice shown by flow cytometry (n = 5 per group). (C) Detection of MPO (green) and citrullinated H3 (pink) in Sh3bp2+/+ and Sh3bp2KI/KI right mandibles 14 days after pulp exposure. Scale bar = 200 μm. Histograms show quantification of MPO, citH3, and colocalization of MPO and citH3 signals normalized to DAPI (blue) from nine periapical and furcation areas in three Sh3bp2+/+ and Sh3bp2KI/KI mice. (D) Coronal and axial planes of μCT images of Sh3bp2KI/KI mice treated with Ly6G antibody or isotype control prior to and after pulp exposure. (E) Quantification of mandible expansion shows significant amelioration after Ly6G antibody treatment in Sh3bp2KI/KI mice compared to no antibody or isotype control (arrows) antibody. Scale bar = 1 mm. Each dot in graphs represents a single biological sample (n = 3–7 per group). Data are presented as mean ± SD. *p < 0.05, **p < 0.01 indicate significant difference by Student's t test (B), (C) and one‐way ANOVA (E).
Source publication
Cherubism (CBM), characterized by expansile jawbones with multilocular fibro‐cystic lesions, is caused by gain‐of‐function mutations in SH3 domain‐binding protein 2 (SH3BP2; mouse orthologue Sh3bp2). Loss of jawbone and dental integrity significantly decrease the quality of life for affected children. Treatment for CBM is limited to multiple surger...
Citations
... Fuiji et al. [58] and co-authors including Ueki and Reichenberger have stated that the mechanism for activation of CBM lesions are still unclear despite the availability of CBM knock-in (KI) mouse models (Sh3bp2 KI/KI); the latter do not show the phenotype of expansive jawbones. ...
Cherubism is nowadays classified as an autoimmune disease and was first described in 1933. Although suspected at that time to be the result of defective tooth development, it was primarily classified as a bone disease caused by a mutation in the SH3BP2 gene. Despite a knock-in mouse model, phenotypic signs in the jaw area were not reproducible in this model. The features of classical cherubism can be attributed to a disturbed formation of the dental placode of the second molar. Since 2019, it has become clear that inhibition of the WNT pathway leads to the accumulation of SH3BP2 via tankyrase inhibition. As the dental placode is triggered via WNT (in epithelia) and MSX1 (in mesenchyme), aplasia of the second and third molars occurs due to a block in the WNT pathway. The mesenchymal part, which occurs prior to the body plan regulation of the WNT/MSX1 pathway, remains unaffected and provides the substrate for the giant cell granuloma. Considering macrophage polarization and the role of the extracellular matrix in general, cherubism is situated in the field of tension between autoimmune diseases and cancer. In this sense, we see the cause of cherubism in a WNT-related dysregulation, which can be proven postnatally in the neural crest-related tooth development of the replacement tooth ridge, both genotypically and phenotypically.
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.
