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Critical Reviews™ in Eukaryotic Gene Expression

Impact factor: 4.111

ISSN Print: 1045-4403
ISSN Online: 2162-6502

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukaryotGeneExpr.v14.i12.10
42 pages

Regulatory Controls for Osteoblast Growth and Differentiation: Role of Runx/Cbfa/AML Factors

Jane B. Lian
Department of Biochemistry University of Vermont
Amjad Javed
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655
Sayyed Kaleem Zaidi
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655
Christopher Lengner
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655
Martin Montecino
Centro de Investigaciones Biomedicas, Facultad de Ciencias Biologicas y Facultad de Medicina, Universidad Andres Bello, Santiago
Andre J. van Wijnen
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655
Janet L. Stein
Department of Biochemistry University of Vermont
Gary Stein
University of Vermont

ABSTRACT

Formation of skeletal elements during embryogenesis and the dynamic remodeling of bone in the adult involve an exquisite interplay of developmental cues, signaling proteins, transcription factors, and their coregulatory proteins that support differentiation of osteogenic lineage cells from the initial mesenchymal progenitor cell to the mature osteocyte in mineralized connective tissue. As regulatory factors continue to be identified, the complexity of the molecular mechanisms that control gene expression in osteoblast lineage cells and drive the osteoblast maturation process are being further appreciated. A central regulator of bone formation is the Runx2 (Cbfa1/AML3) transcription factor which fulfills its role as a master regulatory switch through unique properties for mediating the temporal activation and/or repression of cell growth and phenotypic genes as osteoblasts progress through stages of differentiation. This review examines the multifunctional roles of Runx2 during osteogenesis. Runx2 functions as a "platform protein" that interacts with a spectrum of coregulatory proteins to provide a combinatorial mechanism for integrating cell signaling pathways required for osteoblast differentiation and the tissue-specific regulation of gene expression. In a broader context, it has recently been appreciated that the Runx1 hematopoietic factor and the Runx3 gene associated with neural and gut development are also expressed in the skeleton, although at present our knowledge of their roles in bone formation is limited. Here we discuss the biological functions of Runx factors in promoting cell fate determination and lineage progression, which include (1) regulating gene activation and repression through coregulatory protein interactions and by supporting chromatin remodeling; (2) integrating ECM signaling and cues from developmental, hormonal, and signal transduction pathways by formation of complexes organized in subnuclear domains; and (3) mediating cell growth control. Last, a comprehensive understanding of Runx functions in the skeleton must consider the regulatory mechanisms that control Runx2 transcription and its functional activity through posttranslational modifications.