QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online January 27, 2006
doi: 10.1242/10.1242/jcs.02758

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phillips, J. E. Articles by García, A. J. Search for Related Content PubMed PubMed Citation Articles by Phillips, J. E. Articles by García, A. J. Social Bookmarking                         What's this?

Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation

¹ Wallace H. Coulter Department of Biomedical Engineering and Georgia Tech/Emory Department of Biomedical Engineering, 313 Ferst Drive, Atlanta, GA 30332, USA
² Parker H. Petit Institute for Bioengineering and Bioscience and Georgia Tech/Emory Center for the Engineering of Living Tissues, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA
³ George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, GA 30332, USA

^* Author for correspondence (e-mail: andres.garcia{at}me.gatech.edu)

Accepted 24 October 2005

Glucocorticoid hormones have complex stimulatory and inhibitory effects on skeletal metabolism. Endogenous glucocorticoid signaling is required for normal bone formation in vivo, and synthetic glucocorticoids, such as dexamethasone, promote osteoblastic differentiation in several in vitro model systems. The mechanism by which these hormones induce osteogenesis remains poorly understood. We demonstrate here that the coordinate action of dexamethasone and the osteogenic transcription factor Runx2/Cbfa1 synergistically induces osteocalcin and bone sialoprotein gene expression, alkaline phosphatase activity, and biological mineral deposition in primary dermal fibroblasts. Dexamethasone decreased Runx2 phosphoserine levels, particularly on Ser125, in parallel with the upregulation of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) through a glucocorticoid-receptor-mediated mechanism. Inhibition of MKP-1 abrogated the dexamethasone-induced decrease in Runx2 serine phosphorylation, suggesting that glucocorticoids modulate Runx2 phosphorylation via MKP-1. Mutation of Ser125 to glutamic acid, mimicking constitutive phosphorylation, inhibited Runx2-mediated osteoblastic differentiation, which was not rescued by dexamethasone treatment. Conversely, mutation of Ser125 to glycine, mimicking constitutive dephosphorylation, markedly increased osteoblastic differentiation, which was enhanced by, but did not require, additional dexamethasone supplementation. Collectively, these results demonstrate that dexamethasone induces osteogenesis, at least in part, by modulating the phosphorylation state of a negative-regulatory serine residue (Ser125) on Runx2. This work identifies a novel mechanism for glucocorticoid-induced osteogenic differentiation and provides insights into the role of Runx2 phosphorylation during skeletal development.

Key words: Runx2, Osteogenesis, Dexamethasone, Glucocorticoids, Phosphorylation, Mitogen-activated protein kinase phosphatase-1

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				N. M. Teplyuk, Y. Zhang, Y. Lou, J. R. Hawse, M. Q. Hassan, V. I. Teplyuk, J. Pratap, M. Galindo, J. L. Stein, G. S. Stein, et al. The Osteogenic Transcription Factor Runx2 Controls Genes Involved in Sterol/Steroid Metabolism, Including Cyp11a1 in Osteoblasts Mol. Endocrinol., June 1, 2009; 23(6): 849 - 861. [Abstract] [Full Text] [PDF]

				S. Fatherazi, D. Matsa-Dunn, B.L. Foster, R.B. Rutherford, M.J. Somerman, and R.B. Presland Phosphate Regulates Osteopontin Gene Transcription Journal of Dental Research, January 1, 2009; 88(1): 39 - 44. [Abstract] [Full Text] [PDF]

				A. R. Clark, J. R. S. Martins, and C. R. Tchen Role of Dual Specificity Phosphatases in Biological Responses to Glucocorticoids J. Biol. Chem., September 19, 2008; 283(38): 25765 - 25769. [Abstract] [Full Text] [PDF]

				J. E. Phillips, K. L. Burns, J. M. Le Doux, R. E. Guldberg, and A. J. Garcia Engineering graded tissue interfaces PNAS, August 26, 2008; 105(34): 12170 - 12175. [Abstract] [Full Text] [PDF]

				K. Horsch, H. de Wet, M. M. Schuurmans, F. Allie-Reid, A. C. B. Cato, J. Cunningham, J. M. Burrin, F. S. Hough, and P. A. Hulley Mitogen-Activated Protein Kinase Phosphatase 1/Dual Specificity Phosphatase 1 Mediates Glucocorticoid Inhibition of Osteoblast Proliferation Mol. Endocrinol., December 1, 2007; 21(12): 2929 - 2940. [Abstract] [Full Text] [PDF]

				D. Hendig, M. Arndt, C. Szliska, K. Kleesiek, and C. Gotting SPP1 Promoter Polymorphisms: Identification of the First Modifier Gene for Pseudoxanthoma Elasticum Clin. Chem., May 1, 2007; 53(5): 829 - 836. [Abstract] [Full Text] [PDF]