Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice.

Abstract

Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1α (HIF1α) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice. MMP13 is up-regulated by the Wnt/β-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1α in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1α (∆Hif1α(chon)) with joint instability. Specific loss of HIF1α exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1α lowered transcription factor 4 (TCF4)-β-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1α interacting with β-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, ΔHif1α(chon) mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4-β-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1α-β-catenin interaction is a negative regulator of Wnt signaling and MMP13 transcription, thus reducing catabolism in OA. Our study contributes to the understanding of the role of HIF1α in OA and highlights the HIF1α-β-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage.

DOI: 10.1073/pnas.1514854113

Cite this paper

@article{Bouaziz2016InteractionOH, title={Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice.}, author={Wafa Bouaziz and Johanna Sigaux and Dominique Modrowski and Claire-Sophie Devignes and Thomas Funck-Brentano and Pascal Richette and Hang-Korng Ea and Sylvain Provot and M Cohen-solal and Eric Ha{\"{y}}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2016}, volume={113 19}, pages={5453-8} }