Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone.
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.
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Shibing
S
Yu
Renny T
RT
Franceschi
Min
M
Luo
Jie
J
Fan
Di
D
Jiang
Huiling
H
Cao
Tae-Geon
TG
Kwon
Yumei
Y
Lai
Jian
J
Zhang
Kenneth
K
Patrene
Kurt
K
Hankenson
G David
GD
Roodman
Guozhi
G
Xiao
D051701:Activating Transcription Factor 4 / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
D010281:Parathyroid Hormone; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D000242:Cyclic AMP