Interaction of HIF1a and ß-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice

W Bouaziz, etc
PNAS, 2016

Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1a (HIF1a) 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/ß-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1a in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1a (¿Hif1achon) with joint instability. Specific loss of HIF1a exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1a lowered transcription factor 4 (TCF4)–ß-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1a interacting with ß-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, ¿Hif1achon mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4–ß-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1a–ß-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 HIF1a in OA and highlights the HIF1a–ß-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage.

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doi: 10.1073/pnas.1514854113