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SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion

Zhou, Yi and Mohan, Aron and Moore, Douglas C. and Lin, Liangjun and Zhou, Frank Li and Cao, Jay and Wu, Qian and Qin, Yi-Xian and Reginato, Anthony M. and Ehrlich, Michael G. and Yang, Wentian (2015) SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion. FASEB Journal, 29 (5). pp. 1635-1645. ISSN 0892-6638. https://resolver.caltech.edu/CaltechAUTHORS:20150126-103555501

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Abstract

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-κB 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%), structure model index (+119%), and a decrease of trabecular thickness (Tb.Th) (-34.1%) and trabecular spacing (Tb.Sp) (-41.0%). Biochemical analyses demonstrate that Shp2 is required for RANKL-induced formation of giant multinucleated OCs by up-regulating 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 osteolysis and osteoporosis.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1096/fj.14-260844DOIArticle
http://www.fasebj.org/content/29/5/1635PublisherArticle
http://www.fasebj.org/content/29/5/1635/suppl/DC1PublisherSupplemental Data
Additional Information:© 2015 FASEB. Received for publication October 1, 2014. Accepted for publication December 22, 2014. Published online before print January 15, 2015. The authors thank Dr. Nhiem Tran for critical reading, Ms. Xiaohong Wang for histological section and staining, and Dr. T. Taniguchi for pMX-IRES-GFP and pMX-Nfatc1/IRESGFP constructs. The authors are grateful to Mr. Howard Yang (Moses Brown High School) for assistance in performing experiments and data collection. This work was supported in part by the U.S. National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R21AR57156 (to W.Y.) and NIH National Institute of General Medical Sciences Grant P20 GM103468. This study was also aided by a grant from the Pediatric Orthopaedic Society of North America and the Orthopaedic Research and Education Foundation (to W.Y.), and the U.S. Department of Agriculture Research Service program Grant #5450-51000-046-00D (to J.C.).
Funders:
Funding AgencyGrant Number
National Institute of Arthritis and Musculoskeletal and Skin DiseasesR21AR57156
National Institute of General Medical SciencesP20 GM103468
Pediatric Orthopaedic Society of North AmericaUNSPECIFIED
U.S. Department of Agriculture Research Service5450-51000-046-00D
Orthopaedic Research and Education FoundationUNSPECIFIED
Subject Keywords:Shp2 • M-CSF • RANKL • Nfatc1
Issue or Number:5
Record Number:CaltechAUTHORS:20150126-103555501
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150126-103555501
Official Citation:Yi Zhou, Aron Mohan, Douglas C. Moore, Liangjun Lin, Frank Li Zhou, Jay Cao, Qian Wu, Yi-Xian Qin, Anthony M. Reginato, Michael G. Ehrlich, and Wentian Yang SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion FASEB J May 2015 29:1635-1645; published ahead of print January 15, 2015, doi:10.1096/fj.14-260844
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:54074
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:26 Jan 2015 19:08
Last Modified:03 Oct 2019 07:54

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