title: SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion.
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.
authors.affiliation: *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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: *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.
authors.forename: Aron
authors.initials: A
authors.lastname: Mohan
authors.affiliation: *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.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Moore
authors.affiliation: *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.
authors.forename: Liangjun
authors.initials: L
authors.lastname: Lin
authors.affiliation: *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.
authors.forename: Frank Li
authors.initials: FL
authors.lastname: Zhou
authors.affiliation: *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.
authors.forename: Jay
authors.initials: J
authors.lastname: Cao
authors.affiliation: *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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: *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.
authors.forename: Yi-Xian
authors.initials: YX
authors.lastname: Qin
authors.affiliation: *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.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Reginato
authors.affiliation: *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.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Ehrlich
authors.affiliation: *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.
authors.forename: Wentian
authors.initials: W
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001853:Bone Marrow / Q000254:growth & development* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010022:Osteopetrosis / Q000378:metabolism / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D050778:NFATC Transcription Factors; D053245:RANK Ligand; D012333:RNA, Messenger; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: M-CSF; Nfatc1; RANKL