IL-1 in osteoarthritis: time for a critical review of the literature

Vincent, Tonia L.

doi:10.12688/f1000research.18831.1

Cited by 103 publications

(83 citation statements)

References 78 publications

(85 reference statements)

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“…The direct targeting of pro-inflammatory cytokines-in particular TNFa and IL-1β-and the corresponding receptors, respectively, represents another common therapeutic strategy in OA disease, which, however, have suffered major setbacks in recent years. Although IL-1β receptor antagonists (IL-1β RA) and antibodies, respectively, exhibited striking protection in animal OA models [187,188], clinical studies provided generally disillusioning results [189,190]. Similar findings were reported in the case of TNFa-binding monoclonal antibodies (TNFa mAb), which yielded rather disappointing outcomes in OA patients [191].…”

Section: Pharmacologic Modulation Of Chondrocyte's Behavior and Fatementioning

confidence: 75%

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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Section: Pharmacologic Modulation Of Chondrocyte's Behavior and Fatementioning

confidence: 75%

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

Riegger

2020

IJMS

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“…Despite a strong rationale based on in-vitro studies, evidence to support a direct pathogenic role for IL-1 in osteoarthritis pathogenesis appears, in retrospect, to have been weak. 53 …”

Section: Targeting Inflammation In Osteoarthritismentioning

confidence: 99%

Of mice and men: converging on a common molecular understanding of osteoarthritis

Vincent

2020

The Lancet Rheumatology

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Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Molecular interrogation of disease through ex-vivo tissue analysis, in-vitro studies, and preclinical models have radically reshaped the knowledge landscape. Inflammation in osteoarthritis appears to be distinct from that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism. Nerve growth factor has emerged as a robust target in osteoarthritis pain in phase 2–3 trials. These studies, both positive and negative, align well with those in preclinical surgical models of osteoarthritis, indicating that pathogenic mechanisms identified in mice can lead researchers to valid human targets. Several novel candidate pathways are emerging from preclinical studies that offer hope of future translational impact. Enhancing trust between industry, basic, and clinical scientists will optimise our collective chance of success.

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“…Then, for each donor sample, the untreated control score was subtracted from the FN-f treated score for every gene. The difference in z-score was then averaged over the three donors, ultimately providing three values for every gene representing the normalized expression relative to the control at each time point (3,6, and 18 hours). This matrix was then clustered using k-means clustering with a k of 4.…”

Section: Temporal Clustering Of Genesmentioning

confidence: 99%

“…A major limitation of these studies is that the cells are treated with levels of cytokines in the ng/ml range to obtain a desired response, while (at least in the synovial fluid) IL-1 and TNFα are only present in pg/ml amounts 5 . In addition, recent studies, including failed clinical trials of IL-1 and TNFα inhibition in OA, suggest that multiple pro-inflammatory mediators contribute to OA development, and IL-1 or TNFα may not be the driving factors [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

Reed¹,

Ulici²,

Kim³

et al. 2020

Preprint

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Objective: Fibronectin is a matrix protein that is fragmented during cartilage degradation in osteoarthritis (OA). Treatment of chondrocytes with fibronectin fragments (FN-f) has been used to model OA in vitro, but the system has not been fully characterized. This study sought to define the transcriptional response of chondrocytes to FN-f, and directly compare it to responses traditionally observed in OA.Design: Normal human femoral chondrocytes isolated from tissue donors were treated with either FN-f or PBS (control) for 3, 6, or 18 hours. RNA-seq libraries were compared between time-matched FN-f and control samples in order to identify changes in gene expression over time. Differentially expressed genes were compared to a published OA gene set and used for pathway, transcription factor motif, and kinome analysis.Results: FN-f treatment resulted in 1,224 differentially expressed genes over the time course. Genes that are up-or downregulated in OA were significantly up-(p < 0.00001) or downregulated (p < 0.0004) in response to FN-f. Early response genes were involved in proinflammatory pathways and their promoters were enriched for NF-κB-related motifs, whereas many late response genes were involved in ferroptosis, and their promoters were enriched for Jun-related motifs. Highly upregulated kinases included CAMK1G, IRAK2, and the uncharacterized kinase DYRK3, while growth factor receptors TGFBR2 and FGFR2 were downregulated.Conclusions: FN-f treatment of normal human articular chondrocytes recapitulated many key aspects of the OA chondrocyte phenotype. This in vitro model is promising for future OA studies, especially considering its compatibility with genomics and genome-editing techniques.

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IL-1 in osteoarthritis: time for a critical review of the literature

Cited by 103 publications

References 78 publications

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

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

Of mice and men: converging on a common molecular understanding of osteoarthritis

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

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