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 Dietary Prevention of Obesity-related Disease Research: Grand Forks, ND
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ARS Home Plains Area Grand Forks, North Dakota Grand Forks Human Nutrition Research Center Dietary Prevention of Obesity-related Disease Research Research Publications at this Location





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Title:   Author  item
                                            ZHOU, YI - Boston Children'S Hospitalitem
                                            MOHAN, ARON - Brown Universityitem
                                            MOORE, DOUGLAS - Brown Universityitem
                                            LIN, LIANGJUN - State University Of New York (SUNY)item
                                            ZHOU, FRANK - California Institute Of Technologyitem
                                            Cao, Jayitem
                                            WU, QIAN - University Of Connecticutitem
                                            QIN, YI-XIAN - State University Of New York (SUNY)item
                                            REGINATO, ANTHONY - Brown Universityitem
                                            EHRLICH, MICHAEL - Brown Universityitem
                                            YANG, WENTIAN - Brown University
  Submitted to: Journal of Federation of American Societies for Experimental Biology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 12/22/2014
                                    Publication  Date: 5/1/2015
                                    Publication URL: http://handle.nal.usda.gov/10113/60861Citation: Zhou, Y., Mohan, A., Moore, D., Lin, L., Zhou, F.L., Cao, J.J., Wu, Q., Qin, Y., Reginato, A.M., Ehrlich, M.G., Yang, W. 2015. SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion. Journal of Federation of American Societies for Experimental Biology. 29(5):1635-45.Interpretive Summary: Osteoporosis is the disease caused increased osteoclast activity and bone resorption over osteoblast activity and bone formation. Shp2 is a ubiquitously expressed cytoplasmic protein tyrosine phosphatase and it plays a critical role in regulating RANKL signaling pathway and bone resorption. Using a tissue-specific gene knockout approach, we demonstrated that Shp2 is required for osteoclast formation. We further confirmed that deletion of Shp2 in osteoclast precursors ceases the fusion of osteoclast and decreases bone resorption. Additionally, we found that pharmacological intervention of Shp2 prevents pre-osteoclast fusion in vitro. Our results demonstrate that Shp2 is critical for osteoclastogenesis by promoting pre-osteoclast fusion and Shp2 is potential target for regulating osteoclast activity and treating osteoporosis.
                                Technical Abstract: Genes that regulate osteoclast development and function under physiological and disease conditions remain incompletely understood. Shp2, a ubiquitously expressed cytoplasmic protein tyrosine phosphatase, was implicated in regulating M-CSF and RANKL-evoked signaling, its role in osteoclastogenesis and bone homeostasis, however, is unknown. Using a tissue-specific gene knockout approach, we inactivated Shp2 expression in murine osteoclasts. Shp2 mutant mice are phenotypically osteopetrotic, featuring a marked increase of BV/TV (+42.8%), trabeculae number (+84.1%), structure model index (+119%), and a decrease of Tb.Th (-34.1%) and Tb.Sp (-41.9%). Biochemical analyses demonstrate that Shp2 is required for RANK-induced formation of multinucleated osteoclast by up-regulating the expression of Nfatc1, a master transcription factor that is indispensable for osteoclast differentiation. Shp2 deficiency, however, has minimal effect on M-CSF-dependent survival and proliferation of osteoclast precursors. Instead, Shp2 deletion in osteoclast precursors aborts their fusion and formation of multinucleated osteoclasts and decrease bone matrix resorption. Moreover, pharmacological intervention of Shp2 is sufficient to prevent preosteoclasts from fusion in vitro. These findings strongly suggest that Shp2 is critical for osteoclastogenesis by promoting pre-osteoclast fusion; Shp2 or its signaling partner(s) could potentially serve as pharmacological targets for regulating the population size of osteoclasts locally and/or systematically and thus treating osteoporosis and osteolytic diseases.


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