Editors' ChoiceBONE

Stress Builds Bone

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Sci. Signal.  15 Feb 2011:
Vol. 4, Issue 160, pp. ec46
DOI: 10.1126/scisignal.4160ec46

Previous work had indicated that bone morphogenetic protein 2 (BMP2) stimulated the endoplasmic reticulum (ER) stress response to promote the regulated intramembrane proteolytic activation of OASIS, a transcription factor that stimulates collagen production in osteoblasts. The same group has followed up on these results to show that another arm of the ER stress response also participates in bone building. ER stress stimulates the activity of the kinase PERK, which phosphorylates eukaryotic initiation factor 2α (eIF2α), shutting down most protein translation, with the exception of the transcription factor ATF4, the translation of which is stimulated by phosphorylated eIF2α. Saito et al. show that Perk–/– mice show a bone-deficient phenotype similar to that of Atf4–/– mice and that the abundances of phosphorylated eIF2α, ATF4, and bone-specific targets of ATF4 were all decreased in Perk–/– bones compared with that in wild-type mice. Although osteoblasts from the Perk–/– mice showed a robust induction of the ER chaperone Bip and another transcription factor associated with ER stress, Xbp1, in response to BMP2 or ER stress induced by ER calcium depletion, the induction of ATF4 and its targets was compromised. Reporter gene assays with the cis-acting elements from the osteocalcin (Ocn) gene, which has a Runx2 binding site (OSE2) and an ATF4 binding site (OSE1), showed that induction of the OSE1 reporter construct was specifically compromised in Perk–/– osteoblasts and that the expression of the reporter could be restored by introduction of ATF4. Introduction of ATF4 into Perk–/– osteoblasts also restored the production of OCN and BSP (bone sialoprotein), mineralization, and activity of alkaline phosphatase, which are all indicators of osteoblast differentiation and bone formation. Thus, the ER stress response appears to play a critical role in bone formation.

A. Saito, K. Ochiai, S. Kondo, K. Tsumagari, T. Murakami, D. R. Cavener, K. Imaizumi, Endoplasmic reticulum stress response mediated by the PERK-eIF2α-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J. Biol. Chem. 286, 4809–4818 (2011). [Abstract] [Full Text]

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