Time to be positive about negative data?

Vincent, Tonia L.; Malfait, Anne‐Marie

doi:10.1016/j.joca.2017.01.016

Cited by 6 publications

(6 citation statements)

References 18 publications

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“…Studies are often under-powered and may examine outcomes at only one time point. Animal studies in particular are further confounded by a publication bias towards positive results 81 . RCTs are an expensive way to disprove a major role for a molecule in disease, but the journey nonetheless brings us closer to understanding OA pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

Vincent

2019

F1000Res

102

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The concept of interleukin-1 (IL-1) as a target in osteoarthritis (OA) has been an attractive one for many years. It is a highly potent inducer of cartilage degradation, causing the induction of mRNA and controlling the bioavailability of disease-relevant proteases such as ADAMTS5 and MMP13. It drives synovitis and can induce other disease-relevant genes such as nerve growth factor, a key pain sensitiser in OA. However, the quality of evidence for its involvement in disease is modest. Descriptive studies have demonstrated expression of IL-1α and β in OA cartilage and elevated levels in the synovial fluid of some patients. Agnostic transcriptomic and genomic analyses do not identify IL-1 as a key pathway.In vivomodels show a conflicting role for this molecule; early studies using therapeutic approaches in large animal models show a benefit, but most murine studies fail to demonstrate protection where the ligands (IL-1α/β), the cytokine activator (IL-1–converting enzyme), or the receptor (IL-1R) have been knocked out. Recently, a number of large double-blind randomised controlled clinical studies targeting IL-1 have failed. Enthusiasm for IL-1 as a target in OA is rapidly dwindling.

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Section: Discussionmentioning

confidence: 99%

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

Vincent

2019

F1000Res

102

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“…Nevertheless, we have encountered several other research groups for which diet-induced metabolic overload in mice did not result in OA development either. Hence, it is certainly possible that OA literature has a publication bias concerning this model; a known issue in the OA field 25 and research in general 26 .…”

Section: Discussionmentioning

confidence: 99%

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought

Kozijn

Gierman

Ham

et al. 2018

Osteoarthritis and Cartilage

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Mouse model s u m m a r yObjective: Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was established by various dietary approaches. Design: Wild-type C57BL/6J mice and genetically modified mice (hCRP, LDLr À/À . Leiden and ApoE*3-Leiden.CETP mice) based on C57BL/6J background were used to investigate the contribution of inflammation and altered lipoprotein handling on diet-induced cartilage degradation. High-caloric diets of different macronutrient composition (i.e., high-carbohydrate or high-fat) were given in regimens of varying duration to induce a metabolic phenotype with aggravated cartilage degradation relative to controls. Results: Metabolic phenotypes were confirmed in all studies as mice developed obesity, hypercholesteremia, glucose intolerance and/or insulin resistance. Aggravated cartilage degradation was only observed in two out of the twelve experimental setups, specifically in long-term studies in male hCRP and female ApoE*3Leiden.CETP mice. C57BL/6J and LDLr À/À . Leiden mice did not develop HFD-induced OA under the conditions studied. Osteophyte formation and synovitis scores showed variable results between studies, but also between strains and gender. Conclusions: Long-term feeding of high-caloric diets consistently induced a metabolic phenotype in various C57BL/6J (-based) mouse strains. In contrast, the induction of articular cartilage degradation proved variable, which suggests that an additional trigger might be necessary to accelerate diet-induced OA progression. Gender and genetic modifications that result in a humanized pro-inflammatory state (human CRP) or lipoprotein metabolism (human-E3L.CETP) were identified as important contributing factors. © 2017 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. IntroductionOsteoarthritis (OA) is a progressive joint disease that is characterised by focal loss of articular cartilage, which impedes smooth joint movement and causes stiffness and pain. The most important risk factors for OA are age, gender and obesity. The latter being of specific interest in developed countries, where prolonged life expectancy and a progressive sedentary lifestyle in combination with a high caloric diet is predicted to exponentially increase the number of obese individuals and hence the prevalence of OA The association between knee OA and obesity has been comprehensively studied in humans. Weight loss was found to significantly reduce pain and increase mobility in knee OA patients 3 and reduced the risk of onset of the disease 4 . In obese adults, weight loss combined with exercise appears to be the most promising treatment and is therefore recommended by several international guidelines on the management of metabolic OA 5,6 .Moreover, overweight was found to ...

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“…Overall, success is still elusive. One of the great challenges is the translation of preclinical animal models to the patient situation [ 98 ]. Many compounds with promising results in preclinical and early clinical studies, fail in phase I or II clinical trials.…”

Section: Discussionmentioning

confidence: 99%