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Critical Role of Activating Transcription Factor 4 in the Anabolic Actions of Parathyroid Hormone in Bone
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Critical Role of Activating Transcription Factor 4 in the Anabolic Actions of Parathyroid Hormone in Bone
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Journal Article
Critical Role of Activating Transcription Factor 4 in the Anabolic Actions of Parathyroid Hormone in Bone
2009
Overview
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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
Activating transcription factor 4
/ Activating Transcription Factor 4 - metabolism
/ Activating Transcription Factor 4 - physiology
/ Animals
/ Cell Biology/Gene Expression
/ Collagen
/ Diabetes and Endocrinology/Bone and Mineral Metabolism
/ Female
/ Kinases
/ Medicine
/ Mice
/ Parathyroid Hormone - metabolism
/ Proteins
/ Skeleton
