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

Yu, S and Franceschi, RT and Luo, M and Fan, J and Jiang, D and Cao, H and Kwon, TG and Lai, Y and Zhang, J and Patrene, K and Hankenson, K and Roodman, GD and Xiao, G (2009) Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PLoS ONE, 4 (10).

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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. © 2009 Yu et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Yu, Sshy17@pitt.eduSHY17
Franceschi, RT
Luo, M
Fan, Jjif7@pitt.eduJIF7
Jiang, D
Cao, H
Kwon, TG
Lai, Y
Zhang, J
Patrene, K
Hankenson, K
Roodman, GD
Xiao, G
ContributionContributors NameEmailPitt UsernameORCID
Date: 23 October 2009
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 4
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0007583
Refereed: Yes
MeSH Headings: Activating Transcription Factor 4--metabolism; Activating Transcription Factor 4--physiology; Animals; Bone and Bones--metabolism; Cell Differentiation; Cyclic AMP--metabolism; Female; Gene Expression Regulation; Mice; Mice, Transgenic; Models, Biological; Osteoblasts--metabolism; Parathyroid Hormone--metabolism; Promoter Regions, Genetic; Transcription Factors--metabolism; Up-Regulation
Other ID: NLM PMC2762317
PubMed Central ID: PMC2762317
PubMed ID: 19851510
Date Deposited: 03 Aug 2012 16:20
Last Modified: 02 Feb 2019 16:58


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