Blockade of CD26 Signaling Inhibits Human Osteoclast Development
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- Hiroko Nishida
- Department of PathologyKeio University School of MedicineShinjuku-kuTokyoJapan
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- Hiroshi Suzuki
- Department of PathologyKeio University School of MedicineShinjuku-kuTokyoJapan
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- Hiroko Madokoro
- Department of PathologyKeio University School of MedicineShinjuku-kuTokyoJapan
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- Mutsumi Hayashi
- Department of PathologyKeio University School of MedicineShinjuku-kuTokyoJapan
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- Chikao Morimoto
- Department of Therapy Development and Innovation for Immune Disorders and CancersGraduate School of Medicine, Juntendo UniversityBunkyo-kuTokyoJapan
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- Michiie Sakamoto
- Department of PathologyKeio University School of MedicineShinjuku-kuTokyoJapan
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- Taketo Yamada
- Department of PathologyKeio University School of MedicineShinjuku-kuTokyoJapan
書誌事項
- 公開日
- 2014-05-12
- 資源種別
- journal article
- 権利情報
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- https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model
- DOI
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- 10.1002/jbmr.2277
- 公開者
- Oxford University Press (OUP)
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説明
<jats:title>Abstract</jats:title> <jats:sec> <jats:title> </jats:title> <jats:p>Bone remodeling is maintained by the delicate balance between osteoblasts (OBs) and osteoclasts (OCs). However, the role of CD26 in regulating bone remodeling has not yet been characterized. We herein show that CD26 is preferentially expressed on normal human OCs and is intensely expressed on activated human OCs in osteolytic bone alterations. Macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of NF-κB ligand (sRANKL) induced human OC differentiation, in association with CD26 expression on monocyte-macrophage lineage cells. CD26 expression was accompanied by increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which is crucial for early human OC differentiation. The humanized anti-CD26 monoclonal antibody, huCD26mAb, impaired the formation and function of tartrate-resistant acid phosphatase (TRAP)/CD26 positive multi-nucleated (nuclei > 3) OCs with maturation in the manner of dose-dependency. It was revealed that huCD26mAb inhibits early OC differentiation via the inactivation of MKK3/6, p38 MAPK and subsequent dephosphorylation of microphthalmia-associated transcription factor (mi/Mitf). These inhibitions occur immediately after RANKL binds to RANK on the human OC precursor cells and were demonstrated using the OC functional assays. huCD26mAb subsequently impaired OC maturation and bone resorption by suppressing the expression of TRAP and OC fusion proteins. In addition, p38 MAPK inhibitor also strongly inhibited OC formation and function. Our results suggest that the blockade of CD26 signaling impairs the development of human functional OCs by inhibiting p38 MAPK-mi/Mitf phosphorylation pathway and that targeting human OCs with huCD26mAb may have therapeutic potential for the treatment of osteolytic lesions following metastasis to alleviate bone destruction and reduce total skeletal-related events (SREs). © 2014 American Society for Bone and Mineral Research.</jats:p> </jats:sec>
収録刊行物
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- Journal of Bone and Mineral Research
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Journal of Bone and Mineral Research 29 (11), 2439-2455, 2014-05-12
Oxford University Press (OUP)