SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss

Tomoyuki Mukai, Shu Ishida, Remi Ishikawa, Teruhito Yoshitaka, Mizuho Kittaka, Richard Gallant, Yi Ling Lin, Robert Rottapel, Marco Brotto, Ernst J. Reichenberger, Yasuyoshi Ueki

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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)-a production and receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast differentiation in myeloid cells. TNF-α is expressed in human cherubism lesions, which contain a large number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and TNF-α plays a critical role in inflammatory bone destruction in homozygous cherubism mice (Sh3bp2ΚI/ΚI). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-α-mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-α-mediated osteoclast formation and bone loss. Here, we show that bone marrow-derived M-CSF-dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2ΚI/+) mice are highly responsive to TNF-α and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase Cγ2 (PLCγ2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-α injection model as well as in a human TNF-α 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-α expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF-α-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.

Original languageEnglish (US)
Pages (from-to)2618-2635
Number of pages18
JournalJournal of Bone and Mineral Research
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2014

Keywords

  • Arthritis
  • Cherubism
  • Osteoclast
  • SH3BP2
  • TNF-α

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Mukai, T., Ishida, S., Ishikawa, R., Yoshitaka, T., Kittaka, M., Gallant, R., Lin, Y. L., Rottapel, R., Brotto, M., Reichenberger, E. J., & Ueki, Y. (2014). SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss. Journal of Bone and Mineral Research, 29(12), 2618-2635. https://doi.org/10.1002/jbmr.2295