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First published online 11 March 2003
doi: 10.1242/jcs.00385
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Research Article |
controls extracellular matrix synthesis by epiphyseal chondrocytes
1 Division of Orthopedic Rheumatology, Department of Orthopedic Surgery,
University of Erlangen-Nuremberg, 91054 Erlangen, Germany
2 Molecular Biology Section, Division of Biology, University of California San
Diego, La Jolla, CA 92093, USA
3 Endocrine Unit, Massachusetts General Hospital and Harvard Medical School,
Boston, MA 02114, USA
Author for correspondence (e-mail:
rsjohnson{at}ucsd.edu)
Accepted 23 January 2003
The transcription factor HIF-1
plays a crucial role in modifying
gene expression during low oxygen tension. In a previous study, we
demonstrated that HIF-1 is essential for chondrocyte growth arrest and
survival in vivo. To explore further the role of HIF-1 in cartilage
biology, we undertook studies with primary epiphyseal chondrocytes with a
targeted deletion of HIF-1. In this study, we show that HIF-1 is
necessary for regulating glycolysis under aerobic and anaerobic conditions.
HIF-1-null chondrocytes were unable to maintain ATP levels in hypoxic
microenvironments, indicating a fundamental requirement for this factor for
the regulation of chondrocyte metabolism. Synthesis of the angiogenic factor
vascular endothelial growth factor was also significantly induced by hypoxia,
and this increase is lost in HIF-1-null mutant cells. Under hypoxic
conditions, aggrecan mRNA and protein levels were significantly reduced in
chondrocytes lacking the HIF-1 transcription factor. Interestingly,
strongly increased type-II collagen protein levels were detected in wild-type
cells after 44 hours of hypoxia. In addition, type-II collagen mRNA and
protein levels were strongly decreased under low oxygen in chondrocytes
lacking HIF-1. In summary, our results clearly demonstrate the
importance of HIF-1 in maintenance of anaerobic glycolysis, and thereby
extracellular matrix synthesis, of epiphyseal chondrocytes.
Key words: Chondrocytes, Hypoxia, HIF-1, Extracellular matrix
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