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Title: | Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model | Authors: | Au, M Liu, Z Rong, L Zheng, Y Wen, C |
Issue Date: | Dec-2020 | Source: | Osteoarthritis and cartilage, Dec. 2020, v. 28, no. 12, p. 1559-1571 | Abstract: | 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. |
Keywords: | Endothelin type B receptor Endothelin-1 Osteoarthritis Reactive oxygen species Senescence |
Publisher: | Elsevier | Journal: | Osteoarthritis and cartilage | ISSN: | 1063-4584 | EISSN: | 1522-9653 | DOI: | 10.1016/j.joca.2020.08.006 | Rights: | © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. © 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/ The following publication Au, M., Liu, Z., Rong, L., Zheng, Y., & Wen, C. (2020). Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model. Osteoarthritis and Cartilage, 28(12), 1559-1571 is available at https://doi.org/10.1016/j.joca.2020.08.006. |
Appears in Collections: | Journal/Magazine Article |
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