Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors

Nadiya M. Teplyuk, Mario Galindo, Viktor I. Teplyuk, Jitesh Pratap, Daniel W. Young, David Lapointe, Amjad Javed, Janet L. Stein, Jane B. Lian, Gary S. Stein, Andre J. Van Wijnen

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)27585-27597
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number41
DOIs
StatePublished - Oct 10 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Teplyuk, N. M., Galindo, M., Teplyuk, V. I., Pratap, J., Young, D. W., Lapointe, D., Javed, A., Stein, J. L., Lian, J. B., Stein, G. S., & Van Wijnen, A. J. (2008). Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors. Journal of Biological Chemistry, 283(41), 27585-27597. https://doi.org/10.1074/jbc.M802453200