DICAM inhibits osteoclast differentiation through attenuation of the integrin αVβ3 pathway.

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. Copyright © 2012 American Society for Bone and Mineral Research.

Citation

Youn-Kwan Jung, Seung-Woo Han, Gun-Woo Kim, Jae-Hwan Jeong, Hyun-Ju Kim, Je-Yong Choi. DICAM inhibits osteoclast differentiation through attenuation of the integrin αVβ3 pathway. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2012 Sep;27(9):2024-34

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PMID: 22492581

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