ECTS Abstracts (2015) 1 P225

HIF1[alpha] down-regulates MMP-13 expression through blockade of Wnt canonical signalling

Wafa Bouaziz1,2, Johanna Sigaux1,2, Dominique Modrowski1,2, Caroline Marty1,2, Hang-Korng Ea1,2, Sylvain Provot1,2, Martine Cohen-Solal1,2 & Eric Hay1,2

1NSERM UMR-1132, Paris, France; 2University Paris-Diderot, Paris, France.

Background: Chondrocyte catabolism and MMP-13 expression are triggered by activation of Wnt pathway in osteoarthritis (OA) along with a loss of hypoxic environment. The mechanism by which Wnt/β-catenin pathway is lost down-regulated physiologically is unknown. We speculated that Hypoxia Inducible Factor 1α (HIF1α) regulates Wnt activation and catabolism. Here we investigated the effect of HIF1α/β-catenin interaction in the regulation of MMP-13 expression in OA.

Methods: Murine chondrocytes from WT and ΔHIF1α were cultured with Wnt3a in 21% O2 and 1% O2 (hypoxic) and we analysed the expression of the catabolic markers. The binding of TCF4 to MMP13 regulatory region was assessed by Chip assay. To determine the role of this interaction in vivo, ΔHIF1αchon and HIF1αfl/fl mice underwent DMM and received articular injection of PKF 118-310, an inhibitor of β-catenin/TCF4 interaction.

Results: Hypoxia abolished the Wnt induced decrease of COL2 and the increase of MMP13 expression. HIF1α knockout enhanced the expression of Mmp13 while HIF1α over-expression inhibited it. In hypoxic chondrocytes, Chip assay reveals that HIF1α lowered β-catenin/TCF4 binding to Mmp13 regulatory region by interacting directly with β-catenin. Induced OA resulted in a decreased HIF1α expression in articular cartilage of WT mice. Furthermore, DMM in ΔHIF1αchon mice induce more sever cartilage lesions with higher expression of β-catenin and Mmp13. Local administration of PKF 118-310 prevented cartilage lesions and reduced Mmp13 expression.

Conclusion: Here, we show that HIF1α prevents cartilage degradation through blockade of β-catenin/TCF4 binding and decrease of Mmp-13 expression. HIF1α is an inhibitor of Wnt signalling and should be targeted in OA to reduce chondrocyte catabolism.

Disclosure: The authors declared no competing interests.

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