title: Decreased SH3BP2 inhibits osteoclast differentiation and function.
abstract: 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.
authors: Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors: Teruya
authors: T
authors: Kawamoto
authors: Chun
authors: C
authors: Fan
authors: Robert J
authors: RJ
authors: Gaivin
authors: Michael A
authors: MA
authors: Levine
authors: Steven A
authors: SA
authors: Lietman
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001862:Bone Resorption; D002454:Cell Differentiation; D002460:Cell Line; D055785:Gene Knockdown Techniques; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007527:Isoenzymes; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D034741:RNA, Small Interfering; C484644:Sh3bp2 protein, mouse; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D051966:Phospholipase C gamma