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Molecular and Cellular Biology, May 2007, p. 3337-3352, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01544-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

HOXA10 Controls Osteoblastogenesis by Directly Activating Bone Regulatory and Phenotypic Genes{triangledown}

Mohammad Q. Hassan,1 Rahul Tare,1,{dagger} Suk Hee Lee,1 Matthew Mandeville,1 Brian Weiner,1 Martin Montecino,2 Andre J. van Wijnen,1 Janet L. Stein,1 Gary S. Stein,1 and Jane B. Lian1*

Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655,1 Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias Biologicas, Universidad de Concepcion, Concepcion, Chile2

Received 18 August 2006/ Returned for modification 4 October 2006/ Accepted 9 February 2007

HOXA10 is necessary for embryonic patterning of skeletal elements, but its function in bone formation beyond this early developmental stage is unknown. Here we show that HOXA10 contributes to osteogenic lineage determination through activation of Runx2 and directly regulates osteoblastic phenotypic genes. In response to bone morphogenic protein BMP2, Hoxa10 is rapidly induced and functions to activate the Runx2 transcription factor essential for bone formation. A functional element with the Hox core motif was characterized for the bone-related Runx2 P1 promoter. HOXA10 also activates other osteogenic genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and temporally associates with these target gene promoters during stages of osteoblast differentiation prior to the recruitment of RUNX2. Exogenous expression and small interfering RNA knockdown studies establish that HOXA10 mediates chromatin hyperacetylation and trimethyl histone K4 (H3K4) methylation of these genes, correlating to active transcription. HOXA10 therefore contributes to early expression of osteogenic genes through chromatin remodeling. Importantly, HOXA10 can induce osteoblast genes in Runx2 null cells, providing evidence for a direct role in mediating osteoblast differentiation independent of RUNX2. We propose that HOXA10 activates RUNX2 in mesenchymal cells, contributing to the onset of osteogenesis, and that HOXA10 subsequently supports bone formation by direct regulation of osteoblast phenotypic genes.

* Corresponding author. Mailing address: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0106. Phone: (508) 856-5625. Fax: (508) 856-6800. E-mail: jane.lian{at}umassmed.edu

{triangledown} Published ahead of print on 26 February 2007.

{dagger} Present address: University Orthopedics, Bone and Joint Research Group, General Hospital, Southampton, United Kingdom.

Molecular and Cellular Biology, May 2007, p. 3337-3352, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01544-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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