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J. Biol. Chem., Vol. 279, Issue 28, 29121-29129, July 9, 2004

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Impact of the Mitogen-activated Protein Kinase Pathway on Parathyroid Hormone-related Protein Actions in Osteoblasts^*

Chen Chen, Amy J. Koh, Nabanita S. Datta, Jian Zhang, Evan T. Keller¶, Guozhi Xiao, Renny T. Franceschi||, Nisha J. D'Silva**, and Laurie K. McCauley¶

From the Department of Periodontics Prevention Geriatrics, Unit for Laboratory Animal Medicine, the ^¶Department of Pathology, the ^||Department of Biological Chemistry, and the ^**Department of Oral Medicine Pathology Oncology, University of Michigan, Ann Arbor, Michigan 48109

Parathyroid hormone-related protein (PTHrP) regulates proliferation and differentiation of osteoblastic cells via binding to the parathyroid hormone receptor (PTH-1R). The cAMP-dependent protein kinase A pathway governs the majority of these effects, but recent evidence also implicates the MAPK pathway. MC3T3-E1 subclone 4 cells (MC4) were treated with the MAPK inhibitor U0126 and PTHrP. In differentiated MC4 cells, osteocalcin and bone sialoprotein gene expression were both down-regulated by PTHrP and also by inhibition of the MAPK pathway. PTHrP-mediated down-regulation of PTH-1R mRNA and up-regulation of c-fos mRNA were MAPK-independent, whereas PTHrP stimulation of fra-2 and interleukin-6 (IL-6) mRNA was MAPK-dependent. Luciferase promoter assays revealed that regulation of IL-6 involved the cAMP-dependent protein kinase A and MAPK pathways with a potential minor role of the protein kinase C pathway, and a promoter region containing an activator protein-1 site was necessary for PTHrP-induced IL-6 gene transcription. An alternative pathway, through cAMP/Epac/Rap1/MAPK, mediated ERK phosphorylation but was not sufficient for IL-6 promoter activation. Phosphorylation of the transcription factor CREB was also necessary but not sufficient for PTHrP-mediated IL-6 promoter activity. Most interesting, a bidirectional effect was found with PTHrP increasing phosphorylated ERK in undifferentiated MC4 cells but decreasing phosphorylated ERK in differentiated cells. These data indicate that inactivation of the MAPK pathway shows differential regulation of PTHrP-stimulated activator protein-1 members, blocks PTHrP-stimulated IL-6, and synergistically down-regulates certain osteoblastic markers associated with differentiation. These novel findings indicate that the MAPK pathway plays a selective but important role in the actions of PTHrP.

Received for publication, December 1, 2003 , and in revised form, March 8, 2004.

^* This work was supported by National Institutes of Health Grants DK53904 and CA098513 and by the Center for Craniofacial Regeneration. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Periodontics/Prevention/Geriatrics, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078. Tel.: 734-647-3206; Fax: 734-763-5503; E-mail: mccauley{at}umich.edu.

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