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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 catabo-lism and OA. We studied the role of HIF1α in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1α (ΔHif1α chon) with joint instability. Specific loss of HIF1α exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signal-ing 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.
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https://www.hal.inserm.fr/inserm-01310631
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Submitted on : Monday, May 2, 2016 - 9:09:30 PM
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Wafa Bouaziz, Johanna Sigaux, Dominique Modrowski, Claire-Sophie Devignes, Thomas Funck-Brentano, et al.. Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2016, 113 (19), pp.5453-8. ⟨10.1073/pnas.1514854113⟩. ⟨inserm-01310631⟩

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