Decreased SH3BP2 inhibits osteoclast differentiation and function.

Germline mutations in SH3BP2 gene have been identified in patients with cherubism, a skeletal disorder characterized by excessive osteoclastic bone resorption that is limited to the mandible and maxilla. We previously demonstrated that SH3BP2 overexpression in Raw264.7 cells increased RANKL-induced osteoclastogenesis. Here, we examine the effect of decreased SH3BP2 on osteoclastogenesis. shRNA knockdown of SH3BP2 decreased PLCγ2 phosphorylation and NFATc1 expression, and reduced the expression of osteoclast-specific genes. In BMMs knockdown of SH3BP2 led to reductions in both the number and the surface area of TRAP positive and multinucleated osteoclasts. Bone resorptive activity was also dramatically blocked by shRNA knockdown of SH3BP2. Similarly Sh3bp2(-/-) deficient mice BMMs formed smaller osteoclasts that stained less with TRAP than wild-type mice. Taken together, this study demonstrates that SH3BP2 knockdown significantly decreases osteoclast differentiation and function. These results suggest that SH3BP2 plays a critical role in osteoclastogenesis and is a potential target for suppression of pathologic bone resorption.