A E Kozijn1, L M Gierman2, F van der Ham2, P Mulder2, M C Morrison2, S Kühnast2, R A van der Heijden3, P M Stavro4, A van Koppen2, E J Pieterman2, A M van den Hoek2, R Kleemann2, H M G Princen2, S C Mastbergen5, F P J G Lafeber5, A-M Zuurmond2, I Bobeldijk2, H Weinans6, R Stoop7. 1. Metabolic Health Research, TNO, Leiden, The Netherlands; Department of Orthopaedics, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht University, Utrecht, The Netherlands. 2. Metabolic Health Research, TNO, Leiden, The Netherlands. 3. Department of Pathology and Medical Biology, UMC Groningen, Groningen, The Netherlands. 4. Bunge North America, Saint Louis, United States. 5. Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht University, Utrecht, The Netherlands. 6. Department of Orthopaedics, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Biomechanical Engineering, Delft University of Technology, Delft, The Netherlands. 7. Metabolic Health Research, TNO, Leiden, The Netherlands. Electronic address: Reinout.Stoop@tno.nl.
Abstract
OBJECTIVE: 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-/-. Leiden and ApoE*3Leiden.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-/-. 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.
OBJECTIVE:Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obesepatients. 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-/-. Leiden and ApoE*3Leiden.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-/-. 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.
Authors: Amber T Collins; Guoli Hu; Hunter Newman; Michael H Reinsvold; Monique R Goldsmith; John N Twomey-Kozak; Holly A Leddy; Deepika Sharma; Leyao Shen; Louis E DeFrate; Courtney M Karner Journal: Sci Rep Date: 2021-01-15 Impact factor: 4.379
Authors: Kelly Warmink; Jaqueline L Rios; Devin R van Valkengoed; Nicoline M Korthagen; Harrie Weinans Journal: Int J Mol Sci Date: 2022-03-28 Impact factor: 5.923
Authors: Elise L Donovan; Erika Barboza Prado Lopes; Albert Batushansky; Mike Kinter; Timothy M Griffin Journal: Dis Model Mech Date: 2018-08-31 Impact factor: 5.758