Trends in Genetics
Transcriptional mechanisms in osteoblast differentiation and bone formation
Section snippets
Runx2 and Cbfβ are necessary for bone formation and osteoblast differentiation
Runx2 is the α subunit of a heterodimeric transcription factor, PEBP2/CBF, which is composed of α and β subunits [7]. The α subunit is a structural homologue of the product of the Drosophila segmentation gene runt and contains a conserved region, the Runt domain, which is required for binding to DNA and for dimerization with the β subunit.
In mammals, three α-subunit genes have been identified: Runx2 (also called PEBP2αA, CBFA1 and AML3), Runx1 (also called PEBP2αB, CBFA2 and AML1), and Runx3
Osx is an osteoblast-specific transcription factor
Osx is a zinc-finger-containing transcription factor that is highly specific to osteoblasts in vivo [30]. The amino acid sequence predicts three C2H2-type zinc fingers that have a high degree of identity to similar DNA-binding domains in the transcription factors Sp1, Sp3 and Sp4. Osx has three properties that are typical of transcription factors: it binds strongly to several functional GC-rich sequences, including the consensus binding sites of erythroid Krüppel-like factor (EKLF) and Sp1; the
Molecular pathway of osteoblast differentiation
Based on the characterization of the phenotype of Osx-null mutants, the following model for osteoblast differentiation is proposed (Fig. 4). Osteoblast progenitors in mesenchymal condensations of endochondral and membranous skeletal elements differentiate first into ‘preosteoblasts’, a process in which Runx2 and Cbfβ play an essential role. At this stage, ‘preosteoblasts’ do not express typical osteoblast marker genes. In the membranous and endochondral skeletons, Osx-null preosteoblasts are
Coordination of chondrocyte and osteoblast differentiation during endochondral bone formation
The multistep, parallel pathways of chondrocyte and osteoblast differentiation must be carefully coordinated during the formation of endochondral bone. The endpoint of the chondrocyte-differentiation pathway is the death of hypertrophic chondrocytes. This occurs in conjunction with the degradation of the cartilage ECM and the replacement of dying, hypertrophic chondrocytes by osteoblasts, which then deposit a bone-specific matrix. Although the complex process of endochondral bone formation is
Other transcription factors involved in bone formation
A growing number of transcription factors have been identified that function during bone formation. Msx1 and Msx2 are homeodomain-containing transcription factors that play important roles in skeletal development 37, 38. The role of Msx2 during skull formation was first identified in human genetics studies. In humans, an activating mutation in MSX2 causes Boston-type craniosynostosis, a syndrome that is characterized by increased bone formation around the cranial suture [39].
In Msx2-null mice,
Conclusions
The discovery of Osx and the elucidation of its essential function in bone formation reveal a major new step in the pathway of osteoblast differentiation. Runx2 and its common subunit Cbfβ are needed for an early step in this pathway, whereas Osx is required for a subsequent step, namely the differentiation of preosteoblasts into fully functioning osteoblasts. The finding that Osx-null cells acquire a chondrocytic phenotype implies that Osx is a negative regulator of Sox9 and the chondrocyte
Acknowledgements
Work in the authors' laboratory was supported by NIH PO1 AR42919, NIH RO1 HL41264, the G. Harold and Leila Y. Mathers Charitable Foundation (B.d.C.), and by a grant from Pharmacia SR01–242 (K.N.).
Glossary
Glossary
- Appendicular skeleton:
- limb skeleton.
- Axial skeleton:
- vertebrae and ribs.
- Calvaria:
- skull bones.
- Chondrocytes:
- cells producing cartilage matrix. Cartilage matrix is rich in type II collagen and a highly sulphated cartilage-specific proteoglycan that is stained with alcian blue.
- Clavicle:
- collarbone.
- Hypertrophic chondrocyte:
- large chondrocytes found at the growth plate adjacent to the junction between cartilage and bone.
- Lateral plate mesoderm:
- the mass of mesoderm in the lateral and ventral parts of mouse
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