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SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion
- Zhou, Yi, Mohan, Aron, Moore, Douglas C., Lin, Liangjun, Zhou, Frank Li, Cao, Jay, Wu, Qian, Qin, Yi-Xian, Reginato, Anthony M., Ehrlich, Michael G., Yang, Wentian
- The FASEB Journal 2015 v.29 pp. 1635-1645
- T-lymphocytes, bones, gene targeting, genes, homeostasis, mice, mutants, osteoporosis, protein-tyrosine-phosphatase, resorption, transcription factors
- Genes that regulate osteoclast (OC) development and function in both physiologic and disease conditions remain incompletely understood. Shp2 (the Src homology-2 domain containing protein tyrosine phosphatase 2), a ubiquitously expressed cytoplasmic protein tyrosine phosphatase, is implicated in regulating M-CSF and receptor activator of nuclear factor-kB ligand (RANKL)–evoked signaling; its role in osteoclastogenesis and bone homeostasis, however, remains unknown. Using a tissue-specific gene knockout approach, we inactivated Shp2 expression in murine OCs. Shp2 mutant mice are phenotypically osteopetrotic, featuring a marked increase of bone volume (BV)/total volume(TV) (+42.8%), trabeculae number (Tb.N) (+84.1%), structuremodel index (+119%), and a decrease of trabecular thickness (Tb.Th) (234.1%) and trabecular spacing (Tb.Sp) (241.0%). Biochemical analyses demonstrate that Shp2 is required for RANKLinduced formation of giant ultinucleated OCs by upregulating the expression of nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1), a master transcription factor that is indispensable for terminal OC differentiation. Shp2 deletion, however, has minimal effect on M-CSF–dependent survival and proliferation of OC precursors. Instead, its deficiency aborts the fusion of OC precursors and formation of multinucleated OCs and decreases bone matrix resorption. Moreover, pharmacological intervention of Shp2 is sufficient to prevent preosteoclast fusion in vitro. These findings uncover a novel mechanism through which Shp2 regulates osteoclastogenesis by promoting preosteoclast fusion. Shp2 or its signaling partner(s) could potentially serve as pharmacological target(s) to regulate the population of OCs locally and/or systematically, and thus treat OC-related diseases, such as periprosthetic steolysis and osteoporosis.