A roadmap to target interleukin-6 in osteoarthritis

Wiegertjes, Renske; Loo, Fons A. J. van de; Davidson, E.N. Blaney

doi:10.1093/rheumatology/keaa248

Cited by 82 publications

(60 citation statements)

References 129 publications

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“…Whereas most studies generally focus on the use of one cytokine, a few studies have used a combination of TNF-α, IL-6 and soluble IL-6 receptor (sIL-6R) to better simulate the inflammatory environment existing after knee trauma. Before proceeding to their effects on articular cartilage, we first briefly discuss the two mechanisms, by which IL-6 interacts with target cells [ 190 , 191 ]. IL-6 is capable of binding to the membrane-bound IL-6 receptor (IL-6R), a receptor that alone lacks signaling capacity because it does not contain a signal transduction domain.…”

Section: Results Of the In Vivo Ex Vivo And In Vitro Models That mentioning

confidence: 99%

“…The sIL-6R binds to IL-6 with a similar binding affinity as the membrane-bound IL-6R and rather than competing with the membrane-bound IL-6R, the complex of sIL-6R/IL-6 bind to gp130-expressing cells and, thereby, induce intracellular “trans-signaling”. This mechanism of signaling leads to a more robust activation of the IL-6 intracellular signaling pathway that promotes the chronification of disease [ 191 ].…”

Section: Results Of the In Vivo Ex Vivo And In Vitro Models That mentioning

confidence: 99%

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An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

Khella

Asgarian

Horvath

et al. 2021

IJMS

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Understanding the causality of the post-traumatic osteoarthritis (PTOA) disease process of the knee joint is important for diagnosing early disease and developing new and effective preventions or treatments. The aim of this review was to provide detailed clinical data on inflammatory and other biomarkers obtained from patients after acute knee trauma in order to (i) present a timeline of events that occur in the acute, subacute, and chronic post-traumatic phases and in PTOA, and (ii) to identify key factors present in the synovial fluid, serum/plasma and urine, leading to PTOA of the knee in 23–50% of individuals who had acute knee trauma. In this context, we additionally discuss methods of simulating knee trauma and inflammation in in vivo, ex vivo articular cartilage explant and in vitro chondrocyte models, and answer whether these models are representative of the clinical inflammatory stages following knee trauma. Moreover, we compare the pro-inflammatory cytokine concentrations used in such models and demonstrate that, compared to concentrations in the synovial fluid after knee trauma, they are exceedingly high. We then used the Bradford Hill Framework to present evidence that TNF-α and IL-6 cytokines are causal factors, while IL-1β and IL-17 are credible factors in inducing knee PTOA disease progresssion. Lastly, we discuss beneficial infrastructure for future studies to dissect the role of local vs. systemic inflammation in PTOA progression with an emphasis on early disease.

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Section: Results Of the In Vivo Ex Vivo And In Vitro Models That mentioning

confidence: 99%

Section: Results Of the In Vivo Ex Vivo And In Vitro Models That mentioning

confidence: 99%

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

Khella

Asgarian

Horvath

et al. 2021

IJMS

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“… 152 This finding might suggest that selective inhibition of IL-6 trans-signaling could be a superior treatment strategy as this may inhibit deleterious IL-6 effects in OA, while maintaining protective IL-6 signaling via the classic pathway. 153 Recently, in a phase-3 trial evaluating the efficacy of tocilizumab in hand OA for 12 weeks (n=104), it revealed no more effectiveness than placebo for pain relief (−7.9 vs −9.9 on VAS score in the tocilizumab and placebo groups). 154 …”

Section: Synovitis-driven Endotypementioning

confidence: 99%

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

Oo¹,

Little²,

Duong³

et al. 2021

DDDT

163

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Osteoarthritis (OA) is a complex heterogeneous articular disease with multiple joint tissue involvement of varying severity and no regulatory-agency-approved diseasemodifying drugs (DMOADs). In this review, we discuss the reasons necessitating the development of DMOADs for OA management, the classifications of clinical phenotypes or molecular/mechanistic endotypes from the viewpoint of targeted drug discovery, and then summarize the efficacy and safety profile of a range of targeted drugs in Phase 2 and 3 clinical trials directed to cartilage-driven, bone-driven, and inflammation-driven endotypes. Finally, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers.

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“…IL-6 is one of the most prominent and causal cytokines that is elevated at all stages of knee PTOA [ 3 ], making its inhibition an appealing potential target in the treatment or deterrence of PTOA. IL-6 is secreted by a large number of cells within the joint, including chondrocytes, osteoblasts, synovial fibroblasts, monocytes, and macrophages and is an important modulator of effector CD4 T cells functions (e.g., by inducing the development of IL-17 producing Th17 cells), which are all capable of contributing to a heightened immune response and chronic inflammation [ 141 , 142 ]. IL-6 exerts its effects on target cells via two mechanisms.…”

Section: Anti-inflammatory Therapeutic Interventions To Prevent or Treat Ptoa Of The Knee Jointmentioning

confidence: 99%

“…The binding of IL-6 to sIL-6R has a two-fold effect: it increases the half-life of IL-6 and broadens the range of IL-6 responsiveness due to the universal expression of gp130 on all cell types. Therefore, while IL-6 binds to mIL-6R and sIL-6R with similar binding affinities, IL-6 “trans-signaling” is associated with the development of chronic inflammatory-associated diseases due to the ability of this receptor–ligand pair to interact with membrane-bound gp130 that is expressed by the majority of cell types in the knee joint [ 142 , 144 ].…”

Section: Anti-inflammatory Therapeutic Interventions To Prevent or Treat Ptoa Of The Knee Jointmentioning

confidence: 99%

Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches

Khella

Horvath

Asgarian

et al. 2021

IJMS

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Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.

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A roadmap to target interleukin-6 in osteoarthritis

Cited by 82 publications

References 129 publications

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches

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