TY  - JOUR
AB  - Necroptotic cell death is characterized by an activation of RIPK3 and MLKL that leads to plasma membrane permeabilization and the release of immunostimulatory cellular contents. High levels of chondrocyte death occur following intra-articular trauma, which frequently leads to post-traumatic osteoarthritis development. The aim of this study is to assess necroptosis levels in cartilage post-trauma and to examine whether chondrocyte necroptotic mechanisms may be investigated and modified in vitro. Fractured human and murine cartilage, analysed immunohistochemically for necroptosis marker expression, demonstrated significantly higher levels of RIPK3 and phospho-MLKL than uninjured controls. Primary murine chondrocytes stimulated in vitro with the TNFα and AKT-inhibitor alongside the pan-caspase inhibitor Z-VAD-fmk exhibited a significant loss of metabolic activity and viability, accompanied by an increase in MLKL phosphorylation, which was rescued by further treatment of chondrocytes with necrostatin-1. Transmission electron microscopy demonstrated morphological features of necroptosis in chondrocytes following TNFα and Z-VAD-fmk treatment. Release of dsDNA from necroptotic chondrocytes was found to be significantly increased compared to controls. This study demonstrates that cartilage trauma leads to a high prevalence of necroptotic chondrocyte death, which can be induced and inhibited in vitro, indicating that both necroptosis and its consequential release of immunostimulatory cellular contents are potential therapeutic targets in post-traumatic arthritis treatment.
AU  - Stolberg-Stolberg, Josef
AU  - Sambale, Meike
AU  - Hansen, Uwe
AU  - Schäfer, Alexandra
AU  - Raschke, Michael J.
AU  - Bertrand, Jessica
AU  - Pap, Thomas
AU  - Sherwood, Joanna
DA  - 2020-06-12
DO  - 10.17879/14019506291
KW  - necroptosis
KW  - post-traumatic arthritis
KW  - cell death
KW  - inflammation
KW  - articular cartilage
LA  - eng
N1  - International Journal of Molecular Sciences 21 (2020) 12, 4204, 1-14
N1  - Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster).
N1  - Förderer: Federal Ministry of Education and Research / Projektnummer: 01EC1408F
N1  - Funding organisation: Federal Ministry of Education and Research / Project number: 01EC1408F
N1  - Förderer: Innovative Medicines Initiative / Projektnummer: I-SH121608
N1  - Funding organisation: Innovative Medicines Initiative / Project number: I-SH121608
PY  - 2020-06-12
TI  - Cartilage Trauma Induces Necroptotic Chondrocyte Death and Expulsion of Cellular Contents
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:6-23099740956
Y2  - 2024-11-22T01:02:31
ER  -