| First Author | Bouaziz W | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 19 | Pages | 5453-8 |
| PubMed ID | 27122313 | Mgi Jnum | J:232188 |
| Mgi Id | MGI:5776297 | Doi | 10.1073/pnas.1514854113 |
| Citation | Bouaziz W, et al. (2016) Interaction of HIF1alpha and beta-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice. Proc Natl Acad Sci U S A 113(19):5453-8 |
| abstractText | Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1alpha (HIF1alpha) 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 HIF1alpha in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1alpha (Hif1alpha(chon)) with joint instability. Specific loss of HIF1alpha exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1alpha lowered transcription factor 4 (TCF4)-beta-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1alpha interacting with beta-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, DeltaHif1alpha(chon) mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4-beta-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1alpha-beta-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 HIF1alpha in OA and highlights the HIF1alpha-beta-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage. |
