Editors' ChoiceCell Biology

Stressful Bone Building

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Science Signaling  13 Oct 2009:
Vol. 2, Issue 92, pp. ec330
DOI: 10.1126/scisignal.292ec330

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR); ER stress transducers transmit signals to the nucleus, leading to the expression of UPR-responsive genes and protein degradation in the ER. Murakami et al. generated mice deficient in the ER stress transducer OASIS and found that they exhibited growth retardation and had more fragile skeletons than did wild-type (WT) mice. Whereas there was no difference in the number of osteoclasts (bone-degrading cells) between OASIS–/– mice and WT mice, OASIS–/– mice had fewer osteoblasts (bone-generating cells). OASIS–/– osteoblasts had enlarged ERs that contained accumulated bone matrix proteins, including procollagen 1a1. The abundance of mRNA of genes encoding bone matrix proteins, including Col1a1, which encodes type I collagen, was lower in the bones of OASIS–/– mice than in those of WT mice. Reporter assays and bioinformatics analysis showed that OASIS, or its N-terminal region, bound to the promoter of Col1a1 and drove its expression. The abundance of OASIS mRNA in osteoblasts was low but was increased when cells were exposed to ER stress or to bone morphogenetic protein 2 (BMP2), treatments that also increased the processing of OASIS protein and the translocation of its N-terminal region to the nucleus. BMP2 induced the expression of Col1a1 in WT, but not OASIS–/–, osteoblasts, and OASIS–/– osteoblasts produced less collagen fibers in response to BMP2 than did WT cells. Together, these data suggest that the ER stress response plays a role in bone formation in addition to terminating the UPR, prompting the authors to suggest that the characterization of other ER stress transducers may reveal further physiological roles for the ER stress response.

T. Murakami, A. Saito, S.-i. Hino, S. Kondo, S. Kanemoto, K. Chihara, H. Sekiya, K. Tsumagari, K. Ochiai, K. Yoshinaga, M. Saitoh, R. Nishimura, T. Yoneda, I. Kou, T. Furuichi, S. Ikegawa, M. Ikawa, M. Okabe, A. Wanaka, K. Imaizumi, Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat. Cell Biol. 11, 1205–1211 (2009). [PubMed]

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