Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development.
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 1alpha (HIF1alpha), 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 HIF1alpha leads to increased expression levels of HIF1alpha 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 HIF1alpha. 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.
Pfander
David
D
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Kobayashi
Tatsuya
T
Knight
Melissa C
MC
Zelzer
Elazar
E
Chan
Denise A
DA
Olsen
Bjorn R
BR
Giaccia
Amato J
AJ
Johnson
Randall S
RS
Haase
Volker H
VH
Schipani
Ernestina
E
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D019902:Chondrocytes / Q000166:cytology* / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000502:physiology*; D017930:Genes, Reporter; D006132:Growth Plate / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020287:In Situ Nick-End Labeling; D019426:Integrases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C045073:Cre recombinase; D019426:Integrases; C497446:VHL protein, human