Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice—a translational model for atherosclerosis

Gierman, Lobke; Kühnast, Susan; Koudijs, Angela; Pieterman, Elsbet J.; Kloppenburg, Margreet; Osch, Gerjo J. V. M. van; Stojanovic-Susulic, V.; Huizinga, T.; Princen, H.M.G.; Zuurmond, A.-M.

doi:10.1136/annrheumdis-2013-203248

Cited by 72 publications

(68 citation statements)

References 40 publications

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“…Together with the unfavourable LDL/HDL ratio in these mice, this observation is in agreement with higher OA incidence in women with elevated waist circumference and low HDL cholesterol 53 . Moreover, we previously reported suppression of WTD-induced OA development in ApoE*3Leiden.CETP females upon preventive treatment with the cholesterol-lowering anti-inflammatory drug atorvastatin (Study 12), while cholesterol-lowering alone by ezetimibe did not show this effect 54 . Again, this advocates a role for inflammation in OA development, as previously argued for the hCRP strain.…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

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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“…The lack of associations of diabetic and cholesterol medication use with incident ROA may have resulted from confounding by indication. Therefore, it is still possible that hyperlipidemia[41–43] and diabetes[44] are risk factors for incident ROA. There is the potential that targeting hyperlipidemia and diabetes, other components of metabolic syndrome, might be helpful in preventing incident OA, important questions to address in future research.…”

Section: Discussionmentioning

confidence: 99%

Systolic and pulse pressure associate with incident knee osteoarthritis: data from the Osteoarthritis Initiative

McAlindon

Katz

et al. 2017

Clin Rheumatol

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Objectives We evaluated the relationship of systolic blood pressure, diastolic blood pressure, pulse pressure, and treatment with antihypertensives with knee osteoarthritis incidence in a United States cohort. Methods We performed a longitudinal study (2004 – 2010) nested within the Osteoarthritis Initiative Study including only individuals without knee osteoarthritis at baseline. Systolic blood pressure, diastolic blood pressure and pulse pressure were assessed at baseline, 12-, 24-, and 36-month visits. Knee radiographs at baseline, 12-, 24-, 36- and 48 month visits defined radiographic osteoarthritis, Kellgren and Lawrence grade ≥ 2. We performed logistic regression, adjusting for age, sex, body mass index, NSAID use, number of antihypertensive medications, diabetic medications, and cholesterol medications. Results 1930 people (6040 observations) were included. Annual incidence rates of radiographic osteoarthritis by systolic blood pressure quartiles (lowest to highest) were 2.1%, 3.4%, 3.7%, and 3.7%. Fully adjusted odds ratios of incident radiographic OA for the 2nd–4th quartiles were 1.6, 1.7, and 1.6 relative to the lowest quartile (p for trend = 0.03). Pulse pressure results were similar. There was no association with diastolic blood pressure. Compared to those not taking any antihypertensive medications, those taking ≥ 3 had decreased odds (0.4, 0.1–1.0) of developing incident OA. Conclusions In a United States cohort, higher systolic blood pressure and pulse pressure are associated with increased incidence of radiographic knee osteoarthritis while treatment with ≥ 3 antihypertensive medications was associated with reduced incidence. These findings suggest a new and promising avenue for research on disease modification in knee osteoarthritis.

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“…This model is further supported by data from the investigation of hypercholesterolemia on the progression of OA, using a mouse model that closely mimics human lipoprotein metabolism and dyslipidemia. In the study by Gierman et al, APOE*3L.CETP mice were fed standard Western diets supplemented with either low cholesterol or high cholesterol, or high cholesterol supplemented with either atorvastatin or ezetimibe, an intestinal cholesterol transport inhibitor [40]. Although both drugs produced similar plasma cholesterol-lowering effects, only atorvastatin reduced OA development, which could in part be attributed to the antiinflammatory and immunomodulatory properties of statins [41].…”

Section: The Big Fat Metabolic Messmentioning

confidence: 98%

Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice

Moon

Beier

2015

Curr Rheumatol Rep

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Osteoarthritis causes tremendous individual suffering and staggering societal costs, but due to our limited understanding of the underlying molecular and cellular mechanisms, our avenues for treating this disease are very restricted. Recent years have seen a drastic increase in the use of genetically modified mice to characterize the pathophysiology of osteoarthritis. Many new players and mechanisms driving osteoarthritis pathogenesis have been elucidated, some of which might be strong candidates as therapeutic targets for the human disease. The current review summarizes key findings (selected subjectively by the authors) from mouse osteoarthritis studies over recent years.

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Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice—a translational model for atherosclerosis

Cited by 72 publications

References 40 publications

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

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

Systolic and pulse pressure associate with incident knee osteoarthritis: data from the Osteoarthritis Initiative

Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice

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