title: SH3BP2 is an activator of NFAT activity and osteoclastogenesis.
abstract: Heterozygous activating mutations in exon 9 of SH3BP2 have been found in most patients with cherubism, an unusual genetic syndrome characterized by excessive remodeling of the mandible and maxilla due to spontaneous and excessive osteoclastic bone resorption. Osteoclasts differentiate after binding of sRANKL to RANK induces a number of downstream signaling effects, including activation of the calcineurin/NFAT (nuclear factor of activated T cells) pathway. Here, we have investigated the functional significance of SH3BP2 protein on osteoclastogenesis in the presence of sRANKL. Our results indicate that SH3BP2 both increases nuclear NFATc1 in sRANKL treated RAW 264.7 preosteoclast cells and enhances expression of tartrate resistant acid phosphatase (TRAP), a specific marker of osteoclast differentiation. Moreover, overexpression of SH3BP2 in RAW 264.7 cells potentiates sRANKL-stimulated phosphorylation of PLCgamma1 and 2, thus providing a mechanistic pathway for the rapid translocation of NFATc1 into the nucleus and increased osteoclastogenesis in cherubism.
authors.affiliation: Department of Orthopaedic Surgery, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. lietmas@ccf.org
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lietman
authors.forename: Lihong
authors.initials: L
authors.lastname: Yin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; 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; C484644:Sh3bp2 protein, mouse; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase