Osteoarthritis and cartilage · 2020
Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Au M, Liu Z, Rong L, Zheng Y, Wen C
Аннотация
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 ± 0.21 pg/ml at time zero to 6.47 ± 0.34 pg/ml at 4-month post-surgery. Meanwhile, endothelin type B receptor (ETBR) (53.31 ± 2.42% to 83.8 ± 2.65%) and p16INK4a (10.91 ± 1.07% to 28.2 ± 1.0%) positve chondrocytes 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 ETBR, but not ETAR, lowered the expression of p16INK4a in ET-1 or H2O2-induced chondrocyte senescence model, and mitigated the severity of murine PTOA. Intriguingly, reactive oxygen species (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 ETBR in PTOA.
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 ± 0.21 pg/ml at time zero to 6.47 ± 0.34 pg/ml at 4-month post-surgery. Meanwhile, endothelin type B receptor (ETBR) (53.31 ± 2.42% to 83.8 ± 2.65%) and p16INK4a (10.91 ± 1.07% to 28.2 ± 1.0%) positve chondrocytes 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 ETBR, but not ETAR, lowered the expression of p16INK4a in ET-1 or H2O2-induced chondrocyte senescence model, and mitigated the severity of murine PTOA. Intriguingly, reactive oxygen species (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 ETBR in PTOA.