Conditional deletion of CD98hc inhibits osteoclast development |
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| Authors: | Hideki Tsumura Morihiro Ito Masamichi Takami Miyuki Arai Xiao-Kang Li Toshio Hamatani Arisa Igarashi Shuji Takada Kenji Miyado Akihiro Umezawa Yasuhiko Ito |
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| Institution: | 1. Division of Laboratory Animal Resources, National Research Institute for Child Health and Development, Tokyo, Japan;2. Department of Microbiology, College of Life and Health Science, Chubu University, 1200 Matumoto-Chou, Kasugai-City, Aichi-Prefecture 487-8501, Japan;3. Department of Pharmacology, School of Dentistry, Showa University, Tokyo, Japan;4. Division for Radiation Safety and Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan;5. Department of Obstetrics and Gynaecology, Keio University School of Medicine, Tokyo, Japan;6. Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan;7. Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan;8. Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan |
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| Abstract: | The CD98 heavy chain (CD98hc) regulates virus-induced cell fusion and monocyte fusion, and is involved in amino acid transportation. Here, we examined the role that CD98hc plays in the formation of osteoclasts using CD98hcflox/floxLysM-cre peritoneal macrophages (CD98hc-defect macrophages). Peritoneal macrophages were stimulated with co-cultured with osteoblasts in the presence of 1,25(OH)2 vitamin D3, and thereafter stained with tartrate-resistant acid phosphatase staining solution. The multinucleated osteoclast formation was severely impaired in the peritoneal macrophages isolated from the CD98hc-defect mice compared with those from wild-type mice. CD98hc mediates integrin signaling and amino acid transport through the CD98 light chain (CD98lc). In integrin signaling, suppression of the M-CSF-RANKL-induced phosphorylation of ERK, Akt, JNK and p130Cas were observed at the triggering phase in the CD98h-defect peritoneal macrophages. Moreover, we showed that the general control non-derepressible (GCN) pathway, which was activated by amino acid starvation, was induced by the CD98hc-defect peritoneal macrophages stimulated with RANKL. These results indicate that CD98 plays two important roles in osteoclast formation through integrin signaling and amino acid transport. |
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| Keywords: | CD98 heavy chain Osteoclast formation RANKL Integrin signaling Amino acid transport Amino acid starvation |
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