Increased Myeloid Cell Responses to M-CSF and RANKL Cause Bone Loss and Inflammation in SH3BP2 “Cherubism” Mice

Abstract

While studies of the adaptor SH3BP2 have implicated a role in receptor-mediated signaling in mast cells and lymphocytes, they have failed to identify its function or explain why SH3BP2 missense mutations cause bone loss and inflammation in patients with cherubism. We demonstrate that Sh3bp2 "cherubism" mice exhibit trabecular bone loss, TNF-alpha-dependent systemic inflammation, and cortical bone erosion. The mutant phenotype is lymphocyte independent and can be transferred to mice carrying wild-type Sh3bp2 alleles through mutant fetal liver cells. Mutant myeloid cells show increased responses to M-CSF and RANKL stimulation, and, through mechanisms of increased ERK 1/2 and SYK phosphorylation/activation, they form macrophages that express high levels of TNF-alpha and osteoclasts that are unusually large. M-CSF and RANKL stimulation of myeloid cells that overexpress wild-type SH3BP2 results in similar large osteoclasts. This indicates that the mutant phenotype reflects gain of SH3BP2 function and suggests that SH3BP2 is a critical regulator of myeloid cell responses to M-CSF and RANKL stimulation.

SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions

“…It contributes to the activation of ERK, which is at the bottom of the MAPK-dependent pathway, leading to the production of TNFa and to the activation of the calcineurin/NFAT (nuclear factor of activated T cells) pathway and its downstream effector, NFATc1 (nuclear factor of activated T cells c1 isoform). 38,39 Although these observations give a frame to explain granuloma formation with RAS/MAPK-related genes on the one hand, and SH3BP2 on the other, whether this low penetrant manifestation results from the interference of modifier genes with the RAS/MAPK pathway or from an exogenous stimulus leading to focal development of granuloma in a genetically permissive environment remains unknown.…”

The transient appearance of zipper-like actin superstructures during the fusion of osteoclasts

“…Cherubism is a dominantly inherited syndrome characterized by excessive bone resorption in the jaws and accumulation of inflammatory and/or fibrous tissue in the lower face. Osteoclasts differentiated from bone marrow cells obtained from homozygous cherubism knockin mice carrying a proline to arginine mutation (P416A) in the SH3-binding adaptor protein, SH3BP3, contain ,60 nuclei per cell (Ueki et al, 2007). These observations suggest that osteoclasts have a cell autonomous mechanism to regulate their size.…”

Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages

“…Determinant insights into the mechanism underlying cherubism came from the analysis of the Sh3bp2 P416R genetic mouse model of cherubism (10). Whereas heterozygous cherubic mice showed no significant phenotype, homozygous cherubic animals developed systemic inflammation and severe osteopenia (10,11).…”

“…Whereas heterozygous cherubic mice showed no significant phenotype, homozygous cherubic animals developed systemic inflammation and severe osteopenia (10,11). This phenotype has been linked to exacerbated activities of intracellular signaling components resulting from the accumulation of proteasomeresistant mutant 3BP2 proteins in mouse osteoclasts (12).…”