Abstract
Eukaryotic cells have signalling pathways from the endoplasmic reticulum (ER) to cytosol and nuclei, to avoid excess accumulation of unfolded proteins in the ER. We previously identified a new type of ER stress transducer, OASIS, a bZIP (basic leucine zipper) transcription factor, which is a member of the CREB/ATF family and has a transmembrane domain1,2,3,4,5,6. OASIS is processed by regulated intramembrane proteolysis (RIP) in response to ER stress, and is highly expressed in osteoblasts. OASIS−/− mice exhibited severe osteopenia, involving a decrease in type I collagen in the bone matrix and a decline in the activity of osteoblasts, which showed abnormally expanded rough ER, containing of a large amount of bone matrix proteins. Here we identify the gene for type 1 collagen, Col1a1, as a target of OASIS, and demonstrate that OASIS activates the transcription of Col1a1 through an unfolded protein response element (UPRE)-like sequence in the osteoblast-specific Col1a1 promoter region. Moreover, expression of OASIS in osteoblasts is induced by BMP2 (bone morphogenetic protein 2), the signalling of which is required for bone formation. Additionally, RIP of OASIS is accelerated by BMP2 signalling, which causes mild ER stress. Our studies show that OASIS is critical for bone formation through the transcription of Col1a1 and the secretion of bone matrix proteins, and they reveal a new mechanism by which ER stress-induced signalling mediates bone formation.
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Acknowledgements
We thank G. Karsenty (Columbia University) for providing plasmids (Col1a1 and Osteocalcin as probes for in situ hybridization, and pCMV-ATF4), G. Xiao (University of Pittsburgh, PA, USA) for providing a plasmid (pCMV-Runx2) and L. W. Fisher (National Institutes of Health, USA) for providing an LF41 antibody, M. Tohyama and S. Shiosaka for helpful discussions and critical reading of the manuscript, E. Nishida for technical advice and H. Yamato, H. Murayama,.W. Soma, M. Shimbara, I. Tsuchimochi, T. Kawanami, A. Ikeda, A. Kawai, and Y. Maruyama for technical support. This work was partly supported by grants from the Japan Society for the Promotion of Science KAKENHI (#20059028, #21790184, #20890175, #21790323, #21700410), the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, Takeda Medical Research Foundation and NOVARTIS Foundation (Japan) for the Promotion of Science.
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T.M. performed most of the experiments. A.S., S.H., S.Ko., S.Ka., M.I. and M.O. generated OASIS−/− mice. K.C., H.S., K.T., K.O. and K.Y. performed electron microscopy. M.S., R.N., T.Y., I.K., T.F. and S.I. guided bone experiments. R.N., T.Y., S.I., M.O. and A.W. helped write the manuscript. T.M. and K.I. wrote the manuscript. K.I. supervised the project.
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Murakami, T., Saito, A., Hino, Si. et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol 11, 1205–1211 (2009). https://doi.org/10.1038/ncb1963
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DOI: https://doi.org/10.1038/ncb1963
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