Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-α-induced inflammation and bone loss

Teruhito Yoshitaka, Shu Ishida, Tomoyuki Mukai, Mizuho Kittaka, Ernst J. Reichenberger, Yasuyoshi Ueki

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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 (25mg/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 (0.5mg/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.

Original languageEnglish (US)
Pages (from-to)1170-1182
Number of pages13
JournalJournal of Bone and Mineral Research
Volume29
Issue number5
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Cherubism
Osteitis
src Homology Domains
Carrier Proteins
Tumor Necrosis Factor-alpha
Inflammation
Bone and Bones
Joints
Facial Bones
Lung
Mutation
Inborn Genetic Diseases
Etanercept
Liver
Bone Resorption
Jaw
Skull
Skeleton
Disease Progression
Early Diagnosis

Keywords

  • bone loss
  • cherubism
  • etanercept
  • inflammation
  • TNF-α

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-α-induced inflammation and bone loss. / Yoshitaka, Teruhito; Ishida, Shu; Mukai, Tomoyuki; Kittaka, Mizuho; Reichenberger, Ernst J.; Ueki, Yasuyoshi.

In: Journal of Bone and Mineral Research, Vol. 29, No. 5, 01.01.2014, p. 1170-1182.

Research output: Contribution to journalArticle

Yoshitaka, Teruhito ; Ishida, Shu ; Mukai, Tomoyuki ; Kittaka, Mizuho ; Reichenberger, Ernst J. ; Ueki, Yasuyoshi. / Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-α-induced inflammation and bone loss. In: Journal of Bone and Mineral Research. 2014 ; Vol. 29, No. 5. pp. 1170-1182.
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