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 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 catabolism and OA. We studied the role of HIF1α in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1α (∆Hif1α(chon)) with joint instability. Specific loss of HIF1α exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling 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.
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France;
Wafa
W
Bouaziz
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France; Lariboisière Hospital, Paris 75010, France.
Johanna
J
Sigaux
INSERM UMR-S U1132, Paris 75010, France;
Dominique
D
Modrowski
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France;
Claire-Sophie
CS
Devignes
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France; Lariboisière Hospital, Paris 75010, France.
Thomas
T
Funck-Brentano
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France; Lariboisière Hospital, Paris 75010, France.
Pascal
P
Richette
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France; Lariboisière Hospital, Paris 75010, France.
Hang-Korng
HK
Ea
INSERM UMR-S U1132, Paris 75010, France;
Sylvain
S
Provot
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France; Lariboisière Hospital, Paris 75010, France martine.cohen-solal@inserm.fr.
Martine
M
Cohen-Solal
INSERM UMR-S U1132, Paris 75010, France; Universite Sorbonne Paris-Cité Paris-Diderot Medical School, Paris 75010, France;
Eric
E
Haÿ
D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051176:beta Catenin; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
Wnt signaling; chondrocyte; hypoxia-inducible factor 1α; matrix metalloprotease 13; osteoarthritis