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J. Biol. Chem., Vol. 283, Issue 41, 27585-27597, October 10, 2008

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Runx2 Regulates G Protein-coupled Signaling Pathways to Control Growth of Osteoblast Progenitors^*

Nadiya M. Teplyuk, Mario Galindo¹, Viktor I. Teplyuk, Jitesh Pratap, Daniel W. Young², David Lapointe^¶, Amjad Javed³, Janet L. Stein, Jane B. Lian, Gary S. Stein, and Andre J. van Wijnen⁴

From the Department of Cell Biology and Cancer Center, Bioinformatics Core, Program in Molecular Medicine, and ^¶Information Services, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Runt-related transcription factor 2 (Runx2) controls lineage commitment, proliferation, and anabolic functions of osteoblasts as the subnuclear effector of multiple signaling axes (e.g. transforming growth factor-β/BMP-SMAD, SRC/YES-YAP, and GROUCHO/TLE). Runx2 levels oscillate during the osteoblast cell cycle with maximal levels in G₁. Here we examined what functions and target genes of Runx2 control osteoblast growth. Forced expression of wild type Runx2 suppresses growth of Runx2^-/- osteoprogenitors. Point mutants defective for binding to WW domain or SMAD proteins or the nuclear matrix retain this growth regulatory ability. Hence, key signaling pathways are dispensable for growth control by Runx2. However, mutants defective for DNA binding or C-terminal gene repression/activation functions do not block proliferation. Target gene analysis by Affymetrix expression profiling shows that the C terminus of Runx2 regulates genes involved in G protein-coupled receptor signaling (e.g. Rgs2, Rgs4, Rgs5, Rgs16, Gpr23, Gpr30, Gpr54, Gpr64, and Gna13). We further examined the function of two genes linked to cAMP signaling as follows: Gpr30 that is stimulated and Rgs2 that is down-regulated by Runx2. RNA interference of Gpr30 and forced expression of Rgs2 in each case inhibit osteoblast proliferation. Notwithstanding its growth-suppressive potential, our results surprisingly indicate that Runx2 may sensitize cAMP-related G protein-coupled receptor signaling by activating Gpr30 and repressing Rgs2 gene expression in osteoblasts to increase responsiveness to mitogenic signals.

Received for publication, March 28, 2008 , and in revised form, July 11, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 AR49069 (to A. v. W.) and R01 AR39588, P01 CA82834, and P30 DK32520 (to G. S. S. and J. B. L.). 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.

¹ Present address: Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.

² Present address: Wolf, Greenfield, and Sacks, P.C., 600 Atlantic Ave., Boston, MA 02210.

³ Present address: Institute of Oral Health Research, School of Dentistry, University of Alabama, Birmingham, AL 32294.

⁴ To whom correspondence should be addressed: Dept. of Cell Biology, 55 Lake Ave. North, Worcester, MA 01655-0106. Tel.: 508-856-5625; Fax: 508-856-6800; E-mail: andre.vanwijnen{at}umassmed.edu.

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