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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 ? (TNF-?)-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-? overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-? 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.

SUBMITTER: Yoshitaka T

PROVIDER: S-EPMC4177302 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism.

Yoshitaka Teruhito T Mukai Tomoyuki T Kittaka Mizuho M Alford Lisa M LM Masrani Salome S Ishida Shu S Yamaguchi Ken K Yamada Motohiko M Mizuno Noriyoshi N Olsen Bjorn R BR Reichenberger Ernst J EJ Ueki Yasuyoshi Y

Cell reports 20140915 6

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 P ...[more]

PMID: 25220465

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Project description:Cherubism (CBM), characterized by expansile jawbones with multilocular fibrocystic 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 surgeries to correct facial deformities. Despite significant advances made with CBM knockin (KI) mouse models (Sh3bp2 KI/KI ), the activation mechanisms of CBM lesions remain unknown because mutant mice do not spontaneously develop expansile jawbones. We hypothesize that bony inflammation of an unknown cause triggers jawbone expansion in CBM. To introduce jawbone inflammation in a spatiotemporally controlled manner, we exposed pulp of the first right mandibular molar of 6-week-old Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice. Bacterial invasion from the exposed pulp into root canals led to apical periodontitis in wild-type and mutant mice. The pathogen-associated molecular patterns (PAMPs)-induced inflammation of alveolar bone resulted in jawbone expansion in Sh3bp2 KI/+ and Sh3bp2 KI/KI mice. CBM-like lesions developed exacerbated inflammation with increased neutrophil, macrophage, and osteoclast numbers. These lesions displayed excessive neutrophil extracellular traps (NETs) compared to Sh3bp2 +/+ mice. Expression levels of IL-1β, IL-6, and TNF-α were increased in periapical lesions of Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice and also in plasma and the left untreated mandibles (with no pulp exposure) of Sh3bp2 KI/KI mice, suggesting a systemic upregulation. Ablation of Tlr2/4 signaling or depletion of neutrophils by Ly6G antibodies ameliorated jawbone expansion induced by PAMPs in Sh3bp2 KI/KI mice. In summary, successful induction of CBM-like lesions in jaws of CBM mice is important for studying initiating mechanisms of CBM and for testing potential therapies. Our findings further emphasize a critical role of host immunity in the development of apical periodontitis and the importance of maintaining oral health in CBM patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project description:Cherubism is a genetic disorder of the craniofacial skeleton caused by gain-of-function mutations in the signaling adaptor protein, SH3-domain binding protein 2 (SH3BP2). In a knock-in mouse model for cherubism, we previously demonstrated that homozygous mutant mice develop T/B cell-independent systemic macrophage inflammation leading to bone erosion and joint destruction. Homozygous mice develop multiostotic bone lesions whereas cherubism lesions in humans are limited to jawbones. We identified a critical role of tumor necrosis factor ? (TNF-?) in the development of autoinflammation by creating homozygous TNF-?-deficient cherubism mutants, in which systemic inflammation and bone destruction were rescued. In this study, we examined whether postnatal administration of an anti-TNF-? antagonist can prevent or ameliorate the disease progression in cherubism mice. Neonatal homozygous mutants, in which active inflammation has not yet developed, were treated with a high dose of etanercept (25?mg/kg, twice/week) for 7 weeks. Etanercept-treated neonatal mice showed strong rescue of facial swelling and bone loss in jaws and calvariae. Destruction of joints was fully rescued in the high-dose group. Moreover, the high-dose treatment group showed a significant decrease in lung and liver inflammatory lesions. However, inflammation and bone loss, which were successfully treated by etanercept administration, recurred after etanercept discontinuation. No significant effect was observed in low-dose-treated (0.5?mg/kg, twice/week) and vehicle-treated groups. In contrast, when 10-week-old cherubism mice with fully active inflammation were treated with etanercept for 7 weeks, even the high-dose administration did not decrease bone loss or lung or liver inflammation. Taken together, the results suggest that anti-TNF-? therapy may be effective in young cherubism patients, if treated before the inflammatory phase or bone resorption occurs. Therefore, early genetic diagnosis and early treatment with anti-TNF-? antagonists may be able to prevent or ameliorate cherubism, especially in patients with a mutation in SH3BP2.

Project description:Cherubism (OMIM# 118400) is a genetic disorder with excessive jawbone resorption caused by mutations in SH3 domain binding protein 2 (SH3BP2), a signaling adaptor protein. Studies on the mouse model for cherubism carrying a P416R knock-in (KI) mutation have revealed that mutant SH3BP2 enhances tumor necrosis factor (TNF)-? production and receptor activator of nuclear factor-?B ligand (RANKL)-induced osteoclast differentiation in myeloid cells. TNF-? is expressed in human cherubism lesions, which contain a large number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and TNF-? plays a critical role in inflammatory bone destruction in homozygous cherubism mice (Sh3bp2(KI/KI) ). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-?-mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-?-mediated osteoclast formation and bone loss. Here, we show that bone marrow-derived M-CSF-dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2(KI/+) ) mice are highly responsive to TNF-? and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase C?2 (PLC?2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-? injection model as well as in a human TNF-? transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP-positive multinucleated cell formation. These findings suggest that the SH3BP2 cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF-? expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF-?-induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in cherubism as well as in other inflammatory bone disorders.

Dataset Information

Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism.

Publications

Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism.

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