Role of Matrix Metalloproteinase 13 in Both Endochondral and Intramembranous Ossification during Skeletal Regeneration

Thrombin is a key mediator of fibrin deposition, angiogenesis, and proinflammatory processes. Abnormalities in these processes are primary features of rheumatoid arthritis and osteoarthritis. Matrix metalloproteinase-13 (MMP-13) may contribute to the breakdown of articular cartilage during arthritis. However, the role of thrombin in MMP-13 production in chondrocytes is unknown. In this study, we investigated the intracellular signaling pathways involved in thrombin-induced MMP-13 expression in human chondrocytes. We found that stimulation with thrombin led to increased secretion of MMP-13 in cultured human chondrocytes. Further, this thrombin-induced MMP-13 production was reduced after transfection with siRNAs against protease activated receptors 1 and 3 (PAR1 and PAR3), but not with PAR4 siRNA. Treatment with specific inhibitors for PKCδ, c-Src, EGFR, PI3K, Akt, or AP-1 or with the corresponding siRNAs against these signaling proteins also abolished the thrombin-mediated increase in MMP-13 production in chondrocytes. Our results provide evidence that thrombin acts through the PAR1/PAR3 receptors and activates PKCδand c-Src, resulting in EGFR transactivation and activation of PI3K, Akt, and finally AP-1 on the MMP-13 promoter, thereby contributing to cartilage destruction during arthritis.

Download Full-text

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1514854113 ◽

2016 ◽

Vol 113 (19) ◽

pp. 5453-5458 ◽

Cited By ~ 41

Author(s):

Wafa Bouaziz ◽

Johanna Sigaux ◽

Dominique Modrowski ◽

Claire-Sophie Devignes ◽

Thomas Funck-Brentano ◽

...

Keyword(s):

Articular Cartilage ◽

Matrix Metalloproteinase ◽

Wnt Signaling ◽

Cartilage Degradation ◽

Conditional Knockout ◽

Negative Regulator ◽

Matrix Metalloproteinase 13 ◽

The Impact ◽

Mmp13 Expression

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 (∆Hif1αchon) 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, ΔHif1αchon 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.

Download Full-text