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J. Biol. Chem., Vol. 280, Issue 21, 20274-20285, May 27, 2005

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The Bone-specific Expression of Runx2 Oscillates during the Cell Cycle to Support a G₁-related Antiproliferative Function in Osteoblasts^*

Mario Galindo, Jitesh Pratap, Daniel W. Young, Hayk Hovhannisyan, Hee-Jeong Im, Je-Yong Choi¶, Jane B. Lian, Janet L. Stein, Gary S. Stein, and Andre J. van Wijnen||

From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, the Departments of Biochemistry and Internal Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, Illinois 60612, and the ^¶Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu 700-422, Korea

The Runx2 (CBFA1/AML3/PEBP2A) transcription factor promotes skeletal cell differentiation, but it also has a novel cell growth regulatory activity in osteoblasts. We addressed here whether Runx2 activity is functionally linked to cell cycle-related mechanisms that control normal osteoblast proliferation and differentiation. We found that the levels of Runx2 gene transcription, mRNA and protein, are each up-regulated with cessation of cell growth (i.e. G₀/G₁ transition) in preconfluent MC3T3 osteoblastic cells that do not yet express mature bone phenotypic gene expression. Cell growth regulation of Runx2 is also observed in primary calvarial osteoblasts and other osteoblastic cells with relatively normal cell growth characteristics, but not in osteosarcoma cells (e.g. SAOS-2 and ROS17/2.8). Runx2 levels are cell cycle-regulated in MC3T3 cells with respect to the G₁/S and M/G₁ transitions: oscillates from maximal expression levels during early G₁ to minimal levels during early S phase and mitosis. However, in normal or immortalized (e.g. ATDC5) chondrocytic cells, Runx2 expression is suppressed during quiescence, and Runx2 levels are not regulated during G₁ and S phase in ATDC5 cells. Antisense or small interfering RNA-mediated reduction of the low physiological levels of Runx2 in proliferating MC3T3 cells does not accelerate cell cycle progression. However, forced expression of Runx2 suppresses proliferation of MC3T3 preosteoblasts or C2C12 mesenchymal cells which have osteogenic potential. Forced elevation of Runx2 in synchronized MC3T3 cells causes a delay in G₁. We propose that Runx2 levels and function are biologically linked to a cell growth-related G₁ transition in osteoblastic cells.

Received for publication, December 3, 2004 , and in revised form, March 17, 2005.

^* This work was supported by Grants AR49069, AR39588, and AR48818 from the NIAMS, National Institutes of Health, and by Grant 5P30 DK32520 from the NIDDK, National Institutes of Health. 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 Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Tel.: 508-856-5625; Fax: 508-856-6800; E-mail: andre.vanwijnen{at}umassmed.edu.

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