Programmed cell death and toll-like receptor activation in articular cartilage

Stolberg-Stolberg, Josef; Böttcher, Alfred; Sherwood, J.; Sambale, Meike; Raschke, Michael J.; Pap, Thomas; Bertrand, Juliette

doi:10.1016/j.joca.2018.02.150

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“…Focusing on free nucleic acids, we could show an increased concentration within the supernatant of our necroptotic cells. This released dsDNA has the ability to bind PRRs such as TLR3, perpetuating inflammation and further cell death [ 30 , 31 ]. However, a full analysis of the gene and protein expression profile of chondrocytes undergoing necroptosis would advance our understanding of both the mechanism of necroptosis and of the alterations to anabolic and catabolic processes during chondrocyte necroptosis that may also exacerbate cartilage destruction.…”

Section: Discussionmentioning

confidence: 99%

“…Necroptosis is considered to be highly immunogenically active and is often mediated by the release of DAMPs including nucleic acids [ 28 , 29 ]. Matching pattern-recognition receptors (PRRs) such as Toll-like receptor 3 (TLR3) have been found to mediate inflammatory changes, e.g., through Il-33 and MMP-3 [ 30 , 31 ]. This is supported by recent findings stating that the catabolic activity of live chondrocytes actively contributes to arthritic changes, rather than only the reduced cartilage matrix turnover caused by death of chondrocytes [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Cartilage Trauma Induces Necroptotic Chondrocyte Death and Expulsion of Cellular Contents

Stolberg-Stolberg

Sambale

Hansen

et al. 2020

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%