Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts

Jitesh Pratap, Mario Galindo, S. Kaleem Zaidi, Diana Vradii, Bheem M. Bhat, John A. Robinson, Je Yong Choi, Toshisha Komori, Janet L. Stein, Jane B. Lian, Gary S. Stein, Andre J. Van Wijnen

Research output: Contribution to journalArticle

249 Scopus citations

Abstract

The Runx2 (CBFA1/AML3/PEBP2αA) transcription factor promotes lineage commitment and differentiation by activating bone phenotypic genes in postproliferative osteoblasts. However, the presence of Runx2 in actively dividing osteoprogenitor cells suggests that the protein may also participate in control of osteoblast growth. Here, we show that Runx2 is stringently regulated with respect to cell cycle entry and exit in osteoblasts. We addressed directly the contribution of Runx2 to bone cell proliferation using calvarial osteoblasts from wild-type and Runx2-deficient mice (i.e., Runx2 -/- and Runx2ΔC/ΔC) mice express a protein lacking the Runx2 COOH terminus, which integrates several cell proliferation-related signaling pathways (e.g., Smad, Yes/Src, mitogen-activated protein kinase, and retinoblastoma protein). Calvarial cells but not embryonic fibroblasts from Runx2-/- or Runx2 ΔC/ΔC mutant mice exhibit increased cell growth rates as reflected by elevations of DNA synthesis and G1-S phase markers (e.g., cyclin E). Reintroduction of Runx2 into Runx2-/- calvarial cells by adenoviral delivery restores stringent cell growth control. Thus, Runx2 regulates normal osteoblast proliferation, and the COOH-terminal region is required for this biological function. We propose that Runx2 promotes osteoblast maturation at a key developmental transition by supporting exit from the cell cycle and activating genes that facilitate bone cell phenotype development.

Original languageEnglish (US)
Pages (from-to)5357-5362
Number of pages6
JournalCancer research
Volume63
Issue number17
StatePublished - Sep 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Pratap, J., Galindo, M., Zaidi, S. K., Vradii, D., Bhat, B. M., Robinson, J. A., Choi, J. Y., Komori, T., Stein, J. L., Lian, J. B., Stein, G. S., & Van Wijnen, A. J. (2003). Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts. Cancer research, 63(17), 5357-5362.