The role of SH3BP2 in the pathophysiology of cherubism

Abstract

Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.

Figure 1

Gene map and protein structure of human SH3BP2 indicating mutations in the canonical cherubism mutation interval (amino acids 415-420) and mutations reported in the pleckstrin homology (PH) domain. The mutation in the SH2 domain has been found in tumor tissue of a patient with giant cell tumor. (Modified after Ueki et al., 2001)

Figure 2

Schematic diagram of SH3BP2 interactions and pathway for SH3BP2-induced increase in osteoclastogenesis.

Figure 3

The role of TNF-α, M-CSF and RANKL in the pathogenesis of cherubism. (Modified after Ueki et al., 2007)