title: DICAM inhibits osteoclast differentiation through attenuation of the integrin αVβ3 pathway.
abstract: Dual immunoglobulin (Ig) domain-containing adhesion molecule (DICAM) is involved in cell-cell adhesion through a heterophilic interaction with αVβ3 integrin, which suggests that DICAM may participate in osteoclast differentiation. DICAM was localized in the plasma membrane of RAW264.7 and THP-1 cells, and its expression gradually increased during osteoclastogenesis in mouse bone marrow-derived macrophages (BMMs) treated with receptor activator of nuclear factor κ-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Forced expression of DICAM in BMMs and RAW264.7 cells blocked the generation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. Conversely, knockdown of DICAM by small hairpin RNA (shRNA) increased osteoclast formation in RAW264.7 cells. DICAM-mediated suppression of osteoclast differentiation was in part due to the inhibition of the p38 mitogen-activated protein (MAP) kinase pathway, which was corroborated by a decrease in the expression of c-Fos and nuclear factor of activated T cells (NFAT)c1. Mechanistically, DICAM directly interacted with integrin β3, which inhibited heterodimerization between integrin αV and β3. Exogenous expression of integrin β3 or high-dose M-CSF rescued DICAM-mediated inhibition of osteoclastogenesis, suggesting crosstalk between the integrin β3 and c-Fms pathways. Finally, recombinant DICAM ectodomain suppressed the RANKL- and M-CSF-induced osteoclastogenesis of BMMs. Collectively, these results indicate that DICAM acts as a negative regulator of osteoclast differentiation by suppressing the integrin αVβ3 pathway.
authors.affiliation: Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu, Republic of Korea.
authors.forename: Youn-Kwan
authors.initials: YK
authors.lastname: Jung
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Han
authors.forename: Gun-Woo
authors.initials: GW
authors.lastname: Kim
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Jeong
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Choi
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D053245:RANK Ligand / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C530913:DICAM protein, mouse; D039302:Integrin alphaVbeta3; D053245:RANK Ligand; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases