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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
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