Mechanical force-mediated pathological cartilage thinning is regulated by necroptosis and apoptosis

Zhang, C.; Lin, Sheng; Li, T.; Jiang, Yalong; Huang, Ziwei; Wen, Juan; Cheng, Wen; Li, H.

doi:10.1016/j.joca.2017.03.018

Cited by 39 publications

(48 citation statements)

References 29 publications

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“…While the literature describes additional TNFR1 Complex I destabilization by inhibitor of apoptosis (IAP), transforming growth factor beta-activated kinase 2 (TAK1) or NFκB essential modulator (NEMO) inhibition as essential for necrosome formation and subsequent necroptosis, authors frequently use the protein synthesis inhibitor cylcoheximide [ 40 ]. However, the mechanisms behind TNFα + cycloheximide-induced necroptosis remain unclear and could not be reproduced in this study [ 16 , 25 ]. Instead, we inhibited AKT which is described in detail to promote cell survival via caspase-9, BAD, and FoxO transcription factor down-regulation [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Caspase-independent necroptotic cell death was first analysed in chondrocytes with the pseudoachondroplasia-inked mutation of the cartilage oligomeric matrix protein gene, and so far only leptin has been identified as a factor able to protect chondrocytes from TNFα-induced necroptosis [ 23 , 24 ]. In vivo inhibition of both necroptosis and apoptosis has been shown to attenuate mechanical force-mediated cartilage thinning [ 25 , 26 , 27 ]. This study presents further evidence demonstrating necroptotic activity in articular cartilage from human PTA patients.…”

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%

Section: Introductionmentioning

confidence: 99%

Cartilage Trauma Induces Necroptotic Chondrocyte Death and Expulsion of Cellular Contents

Stolberg-Stolberg

Sambale

Hansen

et al. 2020

IJMS

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“…Nec-1 is a specific small molecule inhibitor of RIPK1 that specifically inhibits phosphorylation of RIPK1. Although numerous studies have demonstrated that Nec-1 attenuates various in vivo and in vitro disease models ( Zhang et al, 2017 ), the effects of Nec-1 on mice with OA are unknown. Our study demonstrated that Nec-1 attenuated OA in vivo and in vitro through the RIPK1/HMGB1/TLR4 and apoptosis pathways.…”

Section: Discussionmentioning

confidence: 99%

Necrostatin-1 Attenuates Trauma-Induced Mouse Osteoarthritis and IL-1β Induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes

Liang

Zhang

et al. 2018

Front. Pharmacol.

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Necrostatin-1 (Nec-1) is a specific small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1) that specifically inhibits phosphorylation of RIPK1. RIPK1 regulates inflammation and cell death by interacting with receptor-interacting serine/threonine protein kinases 3(RIPK3). We hypothesized that Nec-1 may have anti-inflammatory efficacy in patients with osteoarthritis (OA), as the pathophysiology of OA involves the activation of inflammation-related signaling pathways and apoptosis. In this study, we explored the effects of Nec-1 on interleukin (IL)-1β-induced inflammation in mouse chondrocytes and the destabilised medial meniscus (DMM) mouse model. Inhibiting RIPK1 with Nec-1 dramatically suppressed catabolism both in vivo and in vitro, but did not inhibit changes in subchondral bone. Nec-1 abolished the in vitro increases in matrix metalloproteinase (MMP) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTs5) expression induced by IL-1β. However, adding high-mobility group box 1 (HMGB1) partially abrogated this effect, indicating the essential role of HMGB1 and Nec-1 in the protection of primary chondrocytes. Furthermore, Nec-1 decreased the expression of Toll-like receptor 4 (TLR4) and stromal cell-derived factor-1 (SDF-1), and attenuated the interaction between TLR4 and HMGB1. Western blot results suggested that Nec-1 significantly suppressed IL-1β-induced NF-κB transcriptional activity, but not MAPK pathway. Micro-computed tomography, immunohistochemical staining, and Safranin O/Fast Green staining were used in vivo to assess the degree of destruction of OA cartilage. The results show that NEC-1 can significantly reduce the degree of destruction of OA cartilage. Therefore, Nec-1 may be a novel therapeutic candidate to treat OA.

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“…In contrast to necroptosis, which occurs as a regulated form of necrosis, apoptosis does not lead to DAMP release and is therefore considered as a non-inflammatory mode of regulated cell death [113]. While mechanical stress has been shown to induce both primary necrosis and apoptosis [38,82], injury-related necroptosis was found in vivo [122] but seemed to play a minor role in our ex vivo cartilage trauma models under serum-free conditions [113]. We concluded that the activation of the necroptotic pathway might require further co-factors, such as TNFa or certain serum-components [109,123], and concurrent inhibition of the caspase cascade [113].…”

Section: Chondrocyte Death and Cluster Formationmentioning

confidence: 99%

Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment

Riegger

2020

IJMS

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Traumatic injuries of the knee joint result in a wide variety of pathomechanisms, which contribute to the development of so-called posttraumatic osteoarthritis (PTOA). These pathogenetic processes include oxidative stress, excessive expression of catabolic enzymes, release of damage-associated molecular patterns (DAMPs), and synovial inflammation. The present review focuses on the underlying pathomechanisms of PTOA and in particular the behavior and fate of the surviving chondrocytes, comprising chondrocyte metabolism, regulated cell death, and phenotypical changes comprising hypertrophy and senescence. Moreover, possible therapeutic strategies, such as chondroanabolic stimulation, anti-oxidative and anti-inflammatory treatment, as well as novel therapeutic targets are discussed.

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Mechanical force-mediated pathological cartilage thinning is regulated by necroptosis and apoptosis

Cited by 39 publications

References 29 publications

Cartilage Trauma Induces Necroptotic Chondrocyte Death and Expulsion of Cellular Contents

Cartilage Trauma Induces Necroptotic Chondrocyte Death and Expulsion of Cellular Contents

Necrostatin-1 Attenuates Trauma-Induced Mouse Osteoarthritis and IL-1β Induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes

Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment

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