Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation

Tomohiko Murakami, Atsushi Saito, Shin Ichiro Hino, Shinichi Kondo, Soshi Kanemoto, Kazuyasu Chihara, Hiroshi Sekiya, Kenji Tsumagari, Kimiko Ochiai, Kazuya Yoshinaga, Masahiro Saitoh, Riko Nishimura, Toshiyuki Yoneda, Ikuyo Kou, Tatsuya Furuichi, Shiro Ikegawa, Masahito Ikawa, Masaru Okabe, Akio Wanaka, Kazunori Imaizumi

Research output: Contribution to journalArticlepeer-review

208 Citations (Scopus)

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 domain. 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.

Original languageEnglish
Pages (from-to)1205-1211
Number of pages7
JournalNature cell biology
Volume11
Issue number10
DOIs
Publication statusPublished - 2009 Sep 21
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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