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FASEB J. 2015 May;29(5):1635-45. doi: 10.1096/fj.14-260844. Epub 2015 Jan 15.

SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion.

Author information

1
*Stem Cell Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA; Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, New York, USA; Engineering and Applied Science, California Institute of Technology, Pasadena, California, USA; U.S. Department of Agriculture Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, USA; Department of Pathology and Laboratory Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA; and Division of Rheumatology, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA.
2
*Stem Cell Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA; Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, New York, USA; Engineering and Applied Science, California Institute of Technology, Pasadena, California, USA; U.S. Department of Agriculture Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, USA; Department of Pathology and Laboratory Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA; and Division of Rheumatology, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA wyang@lifespan.org.

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 partners could potentially serve as pharmacological targets to regulate the population of OCs locally and/or systematically, and thus treat OC-related diseases, such as periprosthetic osteolysis and osteoporosis.

KEYWORDS:

M-CSF; Nfatc1; RANKL

PMID:
25593124
PMCID:
PMC4415019
DOI:
10.1096/fj.14-260844
[Indexed for MEDLINE]
Free PMC Article

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