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Published 23 May 2005. doi:10.1083/jcb.200412139
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 169, Number 4, 591-601
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Article

FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice



Vionnie W.C. Yu1,2, Gourgen Ambartsoumian1, Lieve Verlinden1, Janet M. Moir1, Josée Prud'homme1, Claude Gauthier1, Peter J. Roughley1,4, and René St-Arnaud1,2,3,4

1 Genetics Unit, Shriners Hospital for Children, Montreal, Quebec, Canada H3G 1A6
2 Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 2T5
3 Department of Medicine, McGill University, Montreal, Quebec, Canada H3A 2T5
4 Department of Surgery, McGill University, Montreal, Quebec, Canada H3A 2T5

Correspondence to René St-Arnaud: rst-arnaud{at}shriners.mcgill.ca

We report the characterization of factor inhibiting activating transcription factor 4 (ATF4)–mediated transcription (FIAT), a leucine zipper nuclear protein. FIAT interacted with ATF4 to inhibit binding of ATF4 to DNA and block ATF4-mediated transcription of the osteocalcin gene in vitro. Transgenic mice overexpressing FIAT in osteoblasts also had reduced osteocalcin gene expression and decreased bone mineral density, bone volume, mineralized volume, trabecular thickness, trabecular number, and decreased rigidity of long bones. Mineral homeostasis, osteoclast number and activity, and osteoblast proliferation and apoptosis were unchanged in transgenics. Expression of osteoblastic differentiation markers was largely unaffected and type I collagen synthesis was unchanged. Mineral apposition rate was reduced in transgenic mice, suggesting that the lowered bone mass was due to a decline in osteoblast activity. This cell-autonomous decrease in osteoblast activity was confirmed by measuring reduced alkaline phosphatase activity and mineralization in primary osteoblast cultures. These results show that FIAT regulates bone mass accrual and establish FIAT as a novel transcriptional regulator of osteoblastic function.

L. Verlinden's present address is Laboratorium voor experimentele geneeskunde en endocrinologie, Onderwijs en Navorsing, Universitaire Ziekenhuizen Gasthuisberg, B-3000 Leuven, Belgium.

Abbreviations used in this paper: ATF4, activating transcription factor 4; bZip, basic domain-leucine zipper; DEXA, dual energy X-ray absorptiometry; EMSA, electrophoretic mobility shift assay; FIAT, factor-inhibiting ATF4-mediated transcription.


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