title: DC-STAMP Is an Osteoclast Fusogen Engaged in Periodontal Bone Resorption.
abstract: Dendritic cell-specific transmembrane protein (DC-STAMP) plays a key role in the induction of osteoclast (OC) cell fusion, as well as DC-mediated immune regulation. While DC-STAMP gene expression is upregulated in the gingival tissue with periodontitis, its pathophysiological roles in periodontitis remain unclear. To evaluate the effects of DC-STAMP in periodontitis, anti-DC-STAMP-monoclonal antibody (mAb) was tested in a mouse model of ligature-induced periodontitis ( n = 6-7/group) where Pasteurella pneumotropica ( Pp)-reactive immune response activated T cells to produce receptor activator of nuclear factor kappa-B ligand (RANKL), which, in turn, promotes the periodontal bone loss via upregulation of osteoclastogenesis. DC-STAMP was expressed on the cell surface of mature multinuclear OCs, as well as immature mononuclear OCs, in primary cultures of RANKL-stimulated bone marrow cells. Anti-DC-STAMP-mAb suppressed the emergence of large, but not small, multinuclear OCs, suggesting that DC-STAMP is engaged in the late stage of cell fusion. Anti-DC-STAMP-mAb also inhibited pit formation caused by RANKL-stimulated bone marrow cells. Attachment of ligature to a second maxillary molar induced DC-STAMP messenger RNA and protein, along with elevated tartrate-resistant acid phosphatase-positive (TRAP+) OCs and alveolar bone loss. As we expected, systemic administration of anti-DC-STAMP-mAb downregulated the ligature-induced alveolar bone loss. Importantly, local injection of anti-DC-STAMP-mAb also suppressed alveolar bone loss and reduced the total number of multinucleated TRAP+ cells in mice that received ligature attachment. Attachment of ligature induced significantly elevated tumor necrosis factor-α, interleukin-1β, and RANKL in the gingival tissue compared with the control site without ligature ( P < 0.05), which was unaffected by local injection with either anti-DC-STAMP-mAb or control-mAb. Neither in vivo anti- Pp IgG antibody nor in vitro anti- Pp T-cell response and resultant production of RANKL was affected by anti-DC-STAMP-mAb. This study illustrated the roles of DC-STAMP in promoting local OC cell fusion without affecting adaptive immune responses to oral bacteria. Therefore, it is plausible that a novel therapeutic regimen targeting DC-STAMP could suppress periodontal bone loss.
authors.affiliation: 1 Department of Periodontology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.|2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|3 Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wisitrasameewong
authors.affiliation: 4 Hiroshima University Graduate School of Biomedical Sciences, Periodontal Medicine, Hiroshima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kajiya
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Movila
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rittling
authors.affiliation: 5 Tokyo Dental College, Tokyo, Chiyoda-ku, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ishii
authors.affiliation: 6 College of Dentistry, The Ohio State University, Columbus, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: 4 Hiroshima University Graduate School of Biomedical Sciences, Periodontal Medicine, Hiroshima, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Mazda
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Torruella
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|7 Araçatuba Dental School, Department of Endodontics, UnivEstadual Paulista, Araçatuba, São Paulo, Brazil.
authors.forename: M M
authors.initials: MM
authors.lastname: Azuma
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|8 LION Corporation, Research and Development Headquarters, Odawara, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Egashira
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: M O
authors.initials: MO
authors.lastname: Freire
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: 9 UCLA, Lab of Molecular Signaling, Division of Oral Biology and Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Wang
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.affiliation: 2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Taubman
authors.affiliation: 10 Department of Periodontology, NOVA Southeastern University College of Dental Medicine, Fort Lauderdale, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation; D002459:Cell Fusion; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010518:Periodontitis / Q000473:pathology*; D053245:RANK Ligand / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; C499636:DC-STAMP protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053245:RANK Ligand
keywords: bone resorption; cell fusion; immunity; mice; osteoclasts; periodontal disease(s)/periodontitis