The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation

Abstract

We have identified a novel zinc finger-containing transcription factor, called Osterix (Osx), that is specifically expressed in all developing bones. In Osx null mice, no bone formation occurs. In endochondral skeletal elements of Osx null mice, mesenchymal cells, together with osteoclasts and blood vessels, invade the mineralized cartilage matrix. However, the mesenchymal cells do not deposit bone matrix. Similarly, cells in the periosteum and in the condensed mesenchyme of membranous skeletal elements cannot differentiate into osteoblasts. These cells do, however, express Runx2/Cbfa1, another transcription factor required for bone formation. In contrast, Osx is not expressed in Runx2/Cbfa1 null mice. Thus, Osx acts downstream of Runx2/Cbfa1. Because Osx null preosteoblasts express typical chondrocyte marker genes, we propose that Runx2/Cbfa1-expressing preosteoblasts are still bipotential cells.

Runx2/Osterix and Zinc Uptake Synergize to Orchestrate Osteogenic Differentiation and Citrate Containing Bone Apatite Formation

“…In particular, Zn 2+ has been shown to stimulate the expression of osteogenic master regulators Runx2 and Osterix 7. We confirmed that supplementing Zn 2+ enhanced mRNA and protein levels of Runx2 and Osterix which was blunted by shZIP1 or TPEN (Figure S2C, Supporting Information).…”

“…The majority of Zn 2+ in the body is stored in the skeleton and released during bone resorption 6. Furthermore, Zn 2+ acts as an activator or coactivator of a variety of proteins involved in osteogenesis including the earliest determinant of osteoblast differentiation runt‐related transcription factor 2 (Runx2) and its downstream target gene Osterix, a zinc finger motif containing transcription factor 7. Additionally, incorporation of zinc into biomaterials has been observed to enhance bone formation and mineralization 8.…”

Efficient bone formation by gene transfer of human LIM mineralization protein-3

“…In particular, BMP-2 was strongly upregulated (58-fold) after 4 days, confirming the hypothesis that the LMP proteins act to stimulate expression and thus secretion of BMPs. 3 OSX, a novel zinc finger-containing transcription factor required for osteoblast differentiatio and bone formation, 28 is upregulated by hLMP-3 27-fold 2 days postinfection, but is expressed at only a seven-fold higher level at 4 days. This result suggests that OSX may be a direct target for regulation by LMP3, which in turn regulates BMP-2.…”

Genetically Engineered Mesenchymal Stem Cells: The Ongoing Research for Bone Tissue Engineering

“…Overexpression of Runx2 and osterix in engineered MSCs may direct osteoblastic lineage differentiation and suppress other lineage differentiation (Merriman et al, 1995;Nakashima et al, 2002). Runx2-engineered MSCs directly enhance the repair of critical-sized calvarial defects when implanted solely (Zheng et al, 2004;Zhao et al, 2007) and form more bone when used in BTE (Zhao et al, 2005;Byers et al, 2006).…”

“…Despite this, Runx2 and BMP2 also produce a strong synergistic effect after both are engineered into MSCs (Yang et al, 2003). Osterix may act downstream of Runx2 (Akiyama et al, 2005), and neither endochondral nor intramembranous bone formation occurs in osterix-null mutant mice (Nakashima et al, 2002). In one study, osterix-engineered BM-MSCs in vivo form five times the amount of new bone than control in healing of the calvarial bone defects in mouse (Tu et al, 2007).…”