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

Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1 alpha (HIF1 alpha) 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/beta-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1 alpha in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of HIF1 alpha (Delta Hif1 alpha(chon)) with joint instability. Specific loss of HIF1 alpha exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1 alpha lowered transcription factor 4 (TCF4)-beta-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1 alpha interacting with alpha-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, Delta HIF1 alpha(chon) mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4-alpha-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1 alpha-alpha-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 HIF1 alpha in OA and highlights the HIF1 alpha-alpha-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage.