Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model.

OBJECTIVES: This study aimed to investigate the role of endothelin-1 (ET-1), originally known as the potent vasoconstrictor, and its receptors in chondrocyte senescence and osteoarthritis (OA) development.

METHOD: Temporal changes of ET-1 and its receptors with OA development were characterized in a posttraumatic OA (PTOA) mouse model at time zero, 1-month and 4-month after surgical induction via destabilization of medial meniscus (DMM). A transgenic ET-1 overexpression (TET-1) mouse model was deployed to assess the impact of upregulated ET-1 on chondrocyte senescence and cartilage degradation. Effects of endothelin receptor blockade on chondrocyte senescence and OA development were further examined both in vitro and in vivo.

RESULTS: Local expression of ET-1 in subchondral bone and synovium upregulated after DMM with an increase of plasma ET-1 level from 3.18 ± 0.21pg/ml at time zero to 6.47 ± 0.34pg/ml at 4-month post-surgery. Meanwhile, the endothelin type B receptor (ETB R)-positive (53.31 ± 2.42% to 83.8 ± 2.65%) and p16INK4a -positive chondrocytes (10.91 ± 1.07% to 28.2 ± 1.0%) accumulated in articular cartilage since 1-month prior to cartilage loss at 4-month post-surgery. Overexpressed ET-1 promoted p16INK4a -positive senescent chondrocytes accumulation and cartilage degradation in TET-1 mice. Selective blockade of ETB R, but not ETA R, lowered the expression of p16INK4a in ET-1 or H2 O2 -induced chondrocyte senescence model, and mitigated the severity of murine PTOA. Intriguingly, ROS scavenger, Vitamin C, could rescue ET-1-induced chondrocyte senescence in vitro associated with restoration of mitochondrial dynamics.

CONCLUSION: ET-1 could induce chondrocytes senescence and cartilage damages via ETB R in PTOA.