|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online May 5, 2004
doi: 10.1242/10.1242/dev.01138
1 Endocrine Unit, Massachusetts General Hospital and Harvard Medical School,
Boston, MA 02114, USA
2 Division of Orthopedic Rheumatology, Department of Orthopedic Surgery,
University of Erlangen-Nuremberg, 91054, Germany
3 Molecular Biology Section, Division of Biology, University of San Diego, San
Diego, CA 92093, USA
4 Department of Cell Biology, Harvard Medical School, Boston, MA 02215,
USA
5 Program in Cancer Biology, Department of Radiation Oncology Stanford
University, Stanford, CA 94305, USA
6 Department of Medicine, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104, USA
* Author for correspondence (e-mail: schipani{at}helix.mgh.harvard.edu)
Accepted 19 February 2004
The von Hippel Lindau tumor suppressor protein (pVHL) is a component of a
ubiquitin ligase that promotes proteolysis of the transcription factor
hypoxia-inducible-factor 1
(HIF1), the key molecule in the
hypoxic response. We have used conditional inactivation of murine VHL
(Vhlh) in all cartilaginous elements to investigate its role in
endochondral bone development. Mice lacking Vhlh in cartilage are
viable, but grow slower than control littermates and develop a severe
dwarfism. Morphologically, Vhlh null growth plates display a
significantly reduced chondrocyte proliferation rate, increased extracellular
matrix, and presence of atypical large cells within the resting zone.
Furthermore, stabilization of the transcription factor HIF1 leads to
increased expression levels of HIF1 target genes in Vhlh null
growth plates. Lastly, newborns lacking both Vhlh and Hif1a
genes in growth plate chondrocytes display essentially the same phenotype as
Hif1a null single mutant mice suggesting that the Vhlh null
phenotype could result, at least in part, from increased activity of
accumulated HIF1. This is the first study reporting the novel and
intriguing findings that pVHL has a crucial role in endochondral bone
development and is necessary for normal chondrocyte proliferation in vivo.
Key words: von Hippel-Lindau tumor suppressor protein, Cartilage development, HIF1
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  Y.-B. Shui, J. M. Arbeit, R. S. Johnson, and D. C. Beebe HIF-1: An Age-Dependent Regulator of Lens Cell Proliferation Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 4961 - 4970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Yang, Q. Sun, Y. Teng, F. Li, T. Weng, and X. Yang PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1{alpha} signaling and endoplasmic reticulum stress Development, November 1, 2008; 135(21): 3587 - 3597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Andre and T. S. Pereira Identification of an Alternative Mechanism of Degradation of the Hypoxia-inducible Factor-1{alpha} J. Biol. Chem., October 24, 2008; 283(43): 29375 - 29384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schipani and T. L. Clemens Hypoxia and the Hypoxia-Inducible Factors in the Skeleton IBMS BoneKEy, August 1, 2008; 5(8): 275 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimada, P. A. Greer, A. P. McMahon, M. L. Bouxsein, and E. Schipani In Vivo Targeted Deletion of Calpain Small Subunit, Capn4, in Cells of the Osteoblast Lineage Impairs Cell Proliferation, Differentiation, and Bone Formation J. Biol. Chem., July 25, 2008; 283(30): 21002 - 21010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lei, S. Mason, D. Liu, Y. Huang, C. Marks, R. Hickey, I. S. Jovin, M. Pypaert, R. S. Johnson, and F. J. Giordano Hypoxia-Inducible Factor-Dependent Degeneration, Failure, and Malignant Transformation of the Heart in the Absence of the von Hippel-Lindau Protein Mol. Cell. Biol., June 1, 2008; 28(11): 3790 - 3803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. VanKoevering and B. O. Williams Transgenic Mouse Strains for Conditional Gene Deletion During Skeletal Development IBMS BoneKEy, May 1, 2008; 5(5): 151 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Provot, D. Zinyk, Y. Gunes, R. Kathri, Q. Le, H. M. Kronenberg, R. S. Johnson, M. T. Longaker, A. J. Giaccia, and E. Schipani Hif-1{alpha} regulates differentiation of limb bud mesenchyme and joint development J. Cell Biol., May 7, 2007; 177(3): 451 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Grimmer, N. Balbus, U. Lang, T. Aigner, T. Cramer, L. Muller, B. Swoboda, and D. Pfander Regulation of Type II Collagen Synthesis during Osteoarthritis by Prolyl-4-Hydroxylases: Possible Influence of Low Oxygen Levels Am. J. Pathol., August 1, 2006; 169(2): 491 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Mack, J. H. Patel, M. P. Biju, V. H. Haase, and M. C. Simon Decreased Growth of Vhl-/- Fibrosarcomas Is Associated with Elevated Levels of Cyclin Kinase Inhibitors p21 and p27 Mol. Cell. Biol., June 1, 2005; 25(11): 4565 - 4578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yun, Q. Lin, and A. J. Giaccia Adaptive Myogenesis under Hypoxia Mol. Cell. Biol., April 15, 2005; 25(8): 3040 - 3055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Biju, A. K. Neumann, S. J. Bensinger, R. S. Johnson, L. A. Turka, and V. H. Haase Vhlh Gene Deletion Induces Hif-1-Mediated Cell Death in Thymocytes Mol. Cell. Biol., October 15, 2004; 24(20): 9038 - 9047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bastepe, L. S. Weinstein, N. Ogata, H. Kawaguchi, H. Juppner, H. M. Kronenberg, and U.-i. Chung Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo PNAS, October 12, 2004; 101(41): 14794 - 14799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Seeman and G. J. Strewler Clinical and Basic Research Papers - May and June 2004 Selections IBMS BoneKEy, July 1, 2004; 1(7): 1 - 3. [Full Text] [PDF]
|
|
