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

Zelzer, Elazar; Glotzer, Donald J.; Hartmann, Christine; Thomas, D.; Fukai, Naomi; Söker, Shay; Olsen, Bjørn R.

doi:10.1016/s0925-4773(01)00428-2

Cited by 305 publications

(273 citation statements)

References 49 publications

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“…Whether CMYC and hypoxia common target genes play a role in leukemogenesis remains to be determined. It has been proposed that AML3, a CBFA subunit specific for bone tissue, is involved in the control of the cellular response to hypoxia (Zelzer et al, 2001). Consistently, a crosstalk between AML1-ETO and the cellular response to hypoxia has recently been described, impacting on the transcriptional control of cellular differentiation (Jiang et al, 2005).…”

Section: Discussionmentioning

confidence: 90%

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

et al. 2006

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The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1a-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein.Functional studies show that TEL-ARNT interacts with HIF1a and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1a/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34 þ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.

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Section: Discussionmentioning

confidence: 90%

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

et al. 2006

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“…Moreover, this recruitment is under the influence of a major angiogenic factor, VEGF [42]. VEGF is made by the terminal hypertrophic chondrocytes under the control of Runx-2 [43] and is linked to the expression of another angiogenic factor, connective tissue growth factor (CTGF) [44]. The injection of a soluble VEGF receptor, the mFlt-1-Fc containing the terminal three Ig repeats of the receptor fused to the Fc portion of IgG, phenocopies the growth plate phenotype of MMP9 −/− mice [45].…”

Section: Mmp9 Is a Key Regulator Of Early Growth Plate Angiogenesis Amentioning

confidence: 99%

Matrix remodeling during endochondral ossification

Ortéga

Behonick

Werb

2004

Trends in Cell Biology

380

312

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Endochondral ossification, the process by which most of the skeleton is formed, is a powerful system for studying various aspects of the biological response to degraded extracellular matrix (ECM). In addition, the dependence of endochondral ossification upon neovascularization and continuous ECM remodeling provides a good model for studying the role of the matrix metalloproteases (MMPs) not only as simple effectors of ECM degradation but also as regulators of active signal-inducers for the initiation of endochondral ossification. The daunting task of elucidating their specific role during endochondral ossification has been facilitated by the development of mice deficient for various members of this family. Here, we discuss the ECM and its remodeling as one level of molecular regulation for the process of endochondral ossification, with special attention to the MMPs.In the past decade, multiple discoveries have facilitated our understanding of skeletal development. Transcription factors and/or growth factors that are involved in the genetic and molecular control of OSTEOGENESIS (see glossary box), CHONDROGENESIS and joint formation have been identified and their pathways partially elucidated [1]. The attention now turns to a different level of molecular regulation -that provided by the extracellular matrix (ECM) of the developing bone and the proteases that remodel it. Recent studies attest to the importance of unique composition of distinct ECMs within the developing skeleton, as well as their influence on cell differentiation and function [2][3][4].Bone develops in two different ways. Mesenchymal cells can directly differentiate into bone by the process of INTRAMEMBRANOUS OSSIFICATION, which is responsible for the formation of most of the craniofacial skeleton. Alternatively, these cells can differentiate into cartilage, which then provides a template for bone morphogenesis by the process of ENDOCHONDRAL OSSIFICATION; this process is responsible for the formation of most of the vertebrate appendicular and axial skeleton ( Figure 1a). Endochondral ossification occurs at two distinct sites in the vertebrate long bone -the primary (diaphyseal) and the secondary (epiphyseal) sites of ossification. Bone development initiates at the primary site. The secondary (epiphyseal) site is under independent control and is ossified later (Figure 1b). During this process, a new structure, the GROWTH PLATE, is formed between the DIAPHYSIS and the EPIPHYSIS by the segregation of CHONDROCYTES at different stages of differentiation. Under the control of signaling through Indian hedgehog (Ihh), bone morphogenetic proteins (BMPs) and fibroblast growth factor 18, a region of resting chondrocytes feeds into a zone of proliferating chondrocytes that then undergo hypertrophy and subsequently apoptosis. The ECM produced by and surrounding the terminally differentiated hypertrophic chondrocytes is calcified, partially degraded by the hypertrophic chondrocytes themselves [5], as well as by CHONDROCLASTS and/or preosteoclasts, and be...

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“…However, this is unlikely because the progression of hypertrophic differentiation can be observed during formation of the secondary center of ossification in the distal epiphyses of MT2-5. Further investigations using the metatarsal model of VEGF protein expression (Zelzer et al, 2001(Zelzer et al, , 2002Maes et al, 2004) and other factors known to regulate chondrocyte hypertrophy and angiogenesis (Schipani et al, 2001) may resolve these issues.…”

Section: Comparative Histomorphology Of Growth Plate Formation and DImentioning

confidence: 99%

Ossification of the mouse metatarsal: Differentiation and proliferation in the presence/absence of a defined growth plate

et al. 2005

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There is significant diversity in growth plate behavior among sites within an individual skeleton and between skeletons of different species. This variation within wild-type animals is an underutilized resource for studying skeletal development. One bone that potentially exhibits the most diverse behavior is the metatarsal. While one end forms a growth plate with an epiphyseal secondary center of ossification as in other long bones, the opposite end undergoes direct ossification in a manner more similar to short bones. Although descriptions of human metatarsal/metacarpal ossification are available, a detailed comparative analysis has yet to be conducted in an animal model amenable to biomolecular analysis. Here we report an analysis of proximal and distal ossification in an age series of mouse metatarsals. Safranin O staining was used for qualitative and quantitative histology, and chondrocyte differentiation and proliferation were analyzed using immunohistochemistry for type X collagen and proliferative cell nuclear antigen expression. We establish that, as in the human, both growth plate formation and direct ossification occur in the mouse metatarsal, with chondrocyte populations showing distinct differentiation patterns at opposite ends of the bone. In addition, growth plate formation is characterized by a peak of proliferation in reserve zone chondrocytes that distinguishes it from both established growth plates and direct ossification. Our analysis demonstrates that the mouse metatarsal is a productive model for investigating natural variation in ossification that can further understanding of vertebrate skeletal development and evolution.

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

Cited by 305 publications

References 49 publications

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

Matrix remodeling during endochondral ossification

Ossification of the mouse metatarsal: Differentiation and proliferation in the presence/absence of a defined growth plate

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