This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yu, S. Articles by Xiao, G. Search for Related Content PubMed PubMed Citation Articles by Yu, S. Articles by Xiao, G.

Parathyroid Hormone Increases Activating Transcription Factor 4 Expression and Activity in Osteoblasts: Requirement for Osteocalcin Gene Expression

Departments of Medicine (S.Y., M.L., X.Z., Y.L., J.Z., G.X.) and Pharmacology (Y.J.), University of Pittsburgh, Pittsburgh, Pennsylvania 15240; and Departments of Periodontics and Oral Medicine (R.T.F., D.J.), School of Dentistry, and Department of Biological Chemistry (R.T.F.), School of Medicine, University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Guozhi Xiao, Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh; Veterans Affairs Pittsburgh Healthcare System, Research and Development, 151-U, Room 2W-111, University Drive C, Pittsburgh, Pennsylvania 15240. E-mail: xiaog{at}upmc.edu.

PTH is an important peptide hormone regulator of calcium homeostasis and osteoblast function. However, its mechanism of action in osteoblasts is poorly understood. Our previous study demonstrated that PTH activates mouse osteocalcin (Ocn) gene 2 promoter through the osteoblast-specific element 1 site, a recently identified activating transcription factor-4 (ATF4) -binding element. In the present study, we examined effects of PTH on ATF4 expression and activity as well as the requirement for ATF4 in the regulation of Ocn by PTH. Results show that PTH elevated levels of ATF4 mRNA and protein in a dose- and time-dependent manner. This PTH regulation requires transcriptional activity but not de novo protein synthesis. PTH also increased binding of nuclear extracts to osteoblast-specific element 1 DNA. PTH stimulated ATF4-dependent transcriptional activity mainly through protein kinase A with a lesser requirement for protein kinase C and MAPK/ERK pathways. Lastly, PTH stimulation of Ocn expression was lost by small interfering RNA down-regulation of ATF4 in MC-4 cells and Atf4^–/– bone marrow stromal cells. Collectively, these studies for the first time demonstrate that PTH increases ATF4 expression and activity and that ATF4 is required for PTH induction of Ocn expression in osteoblasts.