Trends in Genetics
Volume 19, Issue 8, August 2003, Pages 458-466
Journal home page for Trends in Genetics

Transcriptional mechanisms in osteoblast differentiation and bone formation

https://doi.org/10.1016/S0168-9525(03)00176-8Get rights and content

Abstract

Osteoblasts, the cells responsible for bone formation, differentiate from mesenchymal cells. Here, we discuss transcription factors that are involved in regulating the multistep molecular pathway of osteoblast differentiation. Runx2 and Osx, a newly identified zinc-finger-containing protein, are transcription factors that are expressed selectively and at high levels in osteoblasts. Null mutations of either leads to a complete absence of bone in mice. Runx2 plus its companion 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 chondrocyte phenotype implies that Osx is a negative regulator of Sox9 and of the chondrocyte phenotype. This leads to the hypothesis that Osx might have a role in the segregation of osteoblasts from osteochondroprogenitors. We also discuss recent progress in studies of other transcription factors that affect skeletal patterning and development.

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

References (60)

  • G Xiao

    Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2

    J. Biol. Chem.

    (2002)
  • Y Tintut

    Inhibition of osteoblast-specific transcription factor Cbfa1 by the cAMP pathway in osteoblastic cells. Ubiquitin/proteasome-dependent regulation

    J. Biol. Chem.

    (1999)
  • K.W McLarren

    The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor Cbfa1

    J. Biol. Chem.

    (2000)
  • D.M Thomas

    The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation

    Mol. Cell

    (2001)
  • K Nakashima

    The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation

    Cell

    (2002)
  • E Zelzer

    Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2

    Mech. Dev.

    (2001)
  • K Thirunavukkarasu

    The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function

    J. Biol. Chem.

    (2000)
  • G.Q Zhao

    rDlx, a novel distal-less-like homeoprotein is expressed in developing cartilages and discrete neuronal tissues

    Dev. Biol.

    (1994)
  • K Miyama

    A BMP-inducible gene, dlx5, regulates osteoblast differentiation and mesoderm induction

    Dev. Biol.

    (1999)
  • L Li

    Dermo-1: a novel twist-related bHLH protein expressed in the developing dermis

    Dev. Biol.

    (1995)
  • H Gollner

    Impaired ossification in mice lacking the transcription factor Sp3

    Mech. Dev.

    (2001)
  • D.M Ornitz et al.

    FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

    Genes Dev.

    (2002)
  • S Mundlos et al.

    Heritable diseases of the skeleton. Part II: Molecular insights into skeletal development-matrix components and their homeostasis

    FASEB J.

    (1997)
  • Y Ito

    Molecular basis of tissue-specific gene expression mediated by the runt domain transcription factor PEBP2/CBF

    Genes Cells

    (1999)
  • M Inada

    Maturational disturbance of chondrocytes in Cbfa1-deficient mice

    Dev. Dyn.

    (1999)
  • C.A Yoshida

    Core-binding factor beta interacts with Runx2 and is required for skeletal development

    Nat. Genet.

    (2002)
  • M Kundu

    Cbfbeta interacts with Runx2 and has a critical role in bone development

    Nat. Genet.

    (2002)
  • J Miller

    The core-binding factor beta subunit is required for bone formation and hematopoietic maturation

    Nat. Genet.

    (2002)
  • S Takeda

    Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice

    Genes Dev.

    (2001)
  • C Ueta

    Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes

    J. Cell Biol.

    (2001)
  • Cited by (0)

    View full text