title: Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) Regulates Osteoclast Differentiation via the Ca2+/NFATc1 Axis.
abstract: DC-STAMP is a multi-pass transmembrane protein essential for cell-cell fusion between osteoclast precursors during osteoclast (OC) development. DC-STAMP-/- mice have mild osteopetrosis and form mononuclear cells with limited resorption capacity. The identification of an Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) on the cytoplasmic tail of DC-STAMP suggested a potential signaling function. The absence of a known DC-STAMP ligand, however, has hindered the elucidation of downstream signaling pathways. To address this problem, we engineered a light-activatable DC-STAMP chimeric molecule in which light exposure mimics ligand engagement that can be traced by downstream Ca2+signaling. Deletion of the cytoplasmic ITIM resulted in a significant elevation in the amplitude and duration of intracellular Ca2+flux. Decreased NFATc1 expression in DC-STAMP-/- cells was restored by DC-STAMP over-expression. Multiple biological phenotypes including cell-cell fusion, bone erosion, cell mobility, DC-STAMP cell surface distribution, and NFATc1 nuclear translocation were altered by deletion of the ITIM and adjacent amino acids. In contrast, mutations on each of the tyrosine residues surrounding the ITIM showed no effect on DC-STAMP function. Collectively, our results suggest that the ITIM on DC-STAMP is a functional motif that regulates osteoclast differentiation through the NFATc1/Ca2+axis. J. Cell. Physiol. 232: 2538-2549, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Allergy/Immunology and Rheumatology, The University of Rochester, Rochester, New York.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chiu
authors.affiliation: The Center for Musculoskeletal Research, The University of Rochester, Rochester, New York.
authors.forename: Edward
authors.initials: E
authors.lastname: Schwarz
authors.affiliation: Division of Allergy/Immunology and Rheumatology, The University of Rochester, Rochester, New York.
authors.forename: Dongge
authors.initials: D
authors.lastname: Li
authors.affiliation: Microbiology and Immunology, The University of Rochester, Rochester, New York.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The Center for Musculoskeletal Research, The University of Rochester, Rochester, New York.
authors.forename: Tzong-Ren
authors.initials: TR
authors.lastname: Sheu
authors.affiliation: Pathology and Laboratory Medicine, School of Medicine and Dentistry, The University of Rochester, Rochester, New York.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Li
authors.affiliation: Microbiology and Immunology, The University of Rochester, Rochester, New York.|Pathology and Laboratory Medicine, School of Medicine and Dentistry, The University of Rochester, Rochester, New York.
authors.forename: Karen L
authors.initials: KL
authors.lastname: de Mesy Bentley
authors.affiliation: Biostatistic, The University of Rochester, Rochester, New York.
authors.forename: Changyong
authors.initials: C
authors.lastname: Feng
authors.affiliation: Hormones and Development, Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Baoli
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institution of Biomedical Engineering, National Cheng Kung University, Tainan City, Taiwan.
authors.forename: Jhih-Cheng
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Division of Allergy/Immunology and Rheumatology, The University of Rochester, Rochester, New York.
authors.forename: Liz
authors.initials: L
authors.lastname: Albertorio-Saez
authors.affiliation: OB/GYN, Urology, Neuroscience, The University of Rochester, Rochester, New York.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wood
authors.affiliation: Microbiology and Immunology, The University of Rochester, Rochester, New York.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: 1st Affiliated Hospital, Xinxiang Medical University, Weihui City, Henan Province, China.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Allergy/Immunology and Rheumatology, The University of Rochester, Rochester, New York.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Ritchlin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling; D002454:Cell Differentiation; D002459:Cell Fusion; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009154:Mutation; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D010014:Osteolysis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D013997:Time Factors; D014162:Transfection
chemical_list: C499636:DC-STAMP protein, mouse; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494005:Nfatc1 protein, mouse