Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone

Shibing Yu, Renny T. Franceschi, Min Luo, Jie Fan, Di Jiang, Huiling Cao, Tae Geon Kwon, Yumei Lai, Jian Zhang, Kenneth Patrene, Kurt Hankenson, G. David Roodman, Guozhi Xiao

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Parathyroid hormone (PTH) is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice lacking bone-related activating transcription factor 4 (ATF4). Our study demonstrates that ATF4 deficiency suppresses PTH-stimulated osteoblast proliferation and survival and abolishes PTH-induced osteoblast differentiation, which, together, compromise the anabolic response. We further demonstrate that the PTH-dependent increase in osteoblast differentiation is correlated with ATF4-dependent up-regulation of Osterix. This regulation involves interactions of ATF4 with a specific enhancer sequence in the Osterix promoter. Furthermore, actions of PTH on Osterix require this same element and are associated with increased binding of ATF4 to chromatin. Taken together these experiments establish a fundamental role for ATF4 in the anabolic actions of PTH on the skeleton.

Original languageEnglish (US)
Article numbere7583
JournalPloS one
Volume4
Issue number10
DOIs
StatePublished - Oct 23 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Yu, S., Franceschi, R. T., Luo, M., Fan, J., Jiang, D., Cao, H., Kwon, T. G., Lai, Y., Zhang, J., Patrene, K., Hankenson, K., Roodman, G. D., & Xiao, G. (2009). Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PloS one, 4(10), [e7583]. https://doi.org/10.1371/journal.pone.0007583