Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis

Schelbergen, R.; Geven, E.J.; Bosch, M.H. van den; Eriksson, Helena; Leanderson, Tomas; Vogl, Thomas; Roth, Johannes; Loo, Fons A. J. van de; Koenders, Marije I.; Kraan, P.M. van der; Berg, Wim B. van den; Blom, A.B.; Lent, P.L.E.M. van

doi:10.1136/annrheumdis-2014-206517

Cited by 74 publications

(61 citation statements)

References 22 publications

(24 reference statements)

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“…Human chondrocytes produce these molecules, and exposure of cartilage explants to S100A8 and S100A9 promoted catabolic (MMP-1, MMP-3, MMP-13, IL-6, IL-1β) and suppressed anabolic gene expression (aggrecan and Collagen type II) in a TLR-4 dependent manner [104]. Moreover, S100A9 deficient mice exhibited reduced disease in the collagenase model, but not the DMM model of OA, [104, 105] and disease was inhibited by pharmacologically reducing S100A9 expression [106]. The differential effects in these two models were attributed to more robust synovial activation in the collagenase model, which is induced by intra-articular injection of bacterial collagenase leading to instability of connective tissues.…”

Section: Methodsmentioning

confidence: 99%

Inflammation in joint injury and post-traumatic osteoarthritis

Lieberthal

Sambamurthy

Scanzello

2015

Osteoarthritis and Cartilage

380

350

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Inflammation is a variable feature of osteoarthritis (OA), associated with joint symptoms and progression of disease. Signs of inflammation can be observed in joint fluids and tissues from patients with joint injuries at risk for development of post-traumatic osteoarthritis (PTOA). Furthermore, inflammatory mechanisms are hypothesized to contribute to the risk of OA development and progression after injury. Animal models of PTOA have been instrumental in understanding factors and mechanisms involved in chronic progressive cartilage degradation observed after a predisposing injury. Specific aspects of inflammation observed in humans, including cytokine and chemokine production, synovial reaction, cellular infiltration and inflammatory pathway activation, are also observed in models of PTOA. Many of these models are now being utilized to understand the impact of post-injury inflammatory response on PTOA development and progression, including risk of progressive cartilage degeneration and development of chronic symptoms post-injury. As evidenced from these models, a vigorous inflammatory response occurs very early after joint injury but is then sustained at a lower level at the later phases. This early inflammatory response contributes to the development of PTOA features including cartilage erosion and is potentially modifiable, but specific mediators may also play a role in tissue repair. Although the optimal approach and timing of anti-inflammatory interventions after joint injury are yet to be determined, this body of work should provide hope for the future of disease modification tin PTOA.

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Section: Methodsmentioning

confidence: 99%

Inflammation in joint injury and post-traumatic osteoarthritis

Lieberthal

Sambamurthy

Scanzello

2015

Osteoarthritis and Cartilage

380

350

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“…Interestingly, S100A8/A9 was shown not only to activate the catabolic aspects of OA, but additionally promotes the anabolic process of ectopic bone/osteophytes formation, both in the CiOA experimental model and in early human OA, possibly via MMP-mediated remodelling of the cartilage matrix that allows osteophytes to increase in size [133]. This is underlined by the finding that S100A8/A9 induces Wnt signalling, which has been shown to promote bone formation [134].…”

Section: S100 Proteinsmentioning

confidence: 99%

Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease?

Bosch

2018

Clinical and Experimental Immunology

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Summary Osteoarthritis (OA) is the most common joint disease that strongly reduces the quality of life in patients; However, no disease‐modifying therapy is available. For a long time, OA was considered a non‐inflammatory disease that was the result of ‘wear‐and‐tear’ and abnormal mechanics, and therefore many considered the term ‘osteoarthritis’ a misnomer. However, during the last decades the notion arose that inflammation is not only present in the majority of OA patients but, rather, actively involved in the progression of the disease. Influx of immune cells is observed in the synovium and a plethora of inflammatory mediators is present in tissues and fluids from OA patients. These mediators cause the production of degrading enzymes that break down the cartilage matrix, which is the main hallmark of OA. Alarmins, which belong to the group of danger signals, have been implicated in many inflammatory diseases. They are among the first factors to be released upon cell stress due to, for example, infection, damage and inflammation. They attract and activate cells of the immune system and therefore lie at the base of the inflammatory reaction. In this narrative review, an overview of the history of OA, the evolving concept of inflammation as important factor in the OA pathogenesis, and particularly the central role that alarmins play in the initiation and maintenance of the low‐grade inflammatory response in OA, is provided. Moreover, the targeting of alarmins as a promising approach to dampen the inflammation in OA is highlighted.

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“…Lees et al [27■■] showed that a 32-mer peptide of aggrecan, generated by sequential enzymatic cleavage in joints of patients with osteoarthritis, promotes catabolism and suppresses anabolic gene expression via MyD88 and TLR-2 in murine and human chondrocytes, synovial fibroblasts, and macrophages. Another group provided evidence that pharmacologic interference with alarmins may provide therapeutic opportunities [28■■]. The S100A8 and S100A9 proteins can drive cartilage inflammatory activity and catabolic responses via TLR-4, as well as disease progression in the collagenase murine model of osteoarthritis.…”

Section: Damage Associated Molecular Patterns and Alarminsmentioning

confidence: 99%

“…The S100A8 and S100A9 proteins can drive cartilage inflammatory activity and catabolic responses via TLR-4, as well as disease progression in the collagenase murine model of osteoarthritis. These investigators have now used paquinimod, which prevents S100A9/TLR binding, to block synovial inflammatory activity in vitro and ameliorate joint damage in the same model [28■■]. Interference with PRRs and their ligands has not yet been translated to human disease, but these studies provide promise for future developments.…”

Section: Damage Associated Molecular Patterns and Alarminsmentioning

confidence: 99%

Role of low-grade inflammation in osteoarthritis

Scanzello

2017

Current Opinion in Rheumatology

223

151

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Purpose of review-Inflammatory changes in joint tissues can be detected by modern imaging techniques in osteoarthritis patients, but may be clinically subtle compared with many other types of arthritis. These changes associate with disease progression and clinical severity, and many inflammatory mediators may have biomarker utility. Moreover, a number of inflammatory mechanisms play a role in animal models of disease, but it is still not clear which mechanisms predominate and might be therapeutically manipulated most effectively. This review highlights specific examples of recent advances published in the past 18 months that have advanced this field.Recent findings-Clinical investigators now show that synovial inflammation is associated with pain sensitization, and similar to knee osteoarthritis, is a common and important feature of hand osteoarthritis. In addition, recent advances in basic studies demonstrate inflammatory markers and mechanisms related to leukocyte activity, innate immune mechanisms, and the chondrocyteintrinsic inflammatory response that might provide better opportunities for early detection, prognosis, or therapeutic intervention.Summary-Inflammation plays a central role in osteoarthritis pathogenesis, but additional translational work in this field is necessary, as are more clinical trials of anti-inflammatory approaches.

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Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis

Abstract: Prophylactic treatment of paquinimod reduces synovial activation, osteophyte formation and cartilage damage in experimental OA with high synovial activation (CIOA) and ameliorates pathological effects of S100A9 in OA synovium ex vivo.

Cited by 74 publications

References 22 publications

Inflammation in joint injury and post-traumatic osteoarthritis

Inflammation in joint injury and post-traumatic osteoarthritis

Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease?

Role of low-grade inflammation in osteoarthritis

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