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 α (TNF-α) in the development of autoinflammation by creating homozygous TNF-α-deficient
cherubism mutants, in which systemic
inflammation and bone destruction were rescued. In this study, we examined whether postnatal administration of an anti-TNF-α 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-α
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-α antagonists may be able to prevent or ameliorate
cherubism, especially in patients with a mutation in SH3BP2.