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Purpose: A growing body of evidence suggests that osteoarthritis (OA) is rather a “metabolic disorder” in which various interrelated metabolic mediators contribute to the initiation and progression of the disease process. One such metabolic risk factor could be high cholesterol levels in the body. The primary objective of this study is to delineate how abnormal cholesterol levels effects the cartilage biology and its relation to OA development. Further, in this study we tested whether hypercholesterolemia -induced mitochondrial DNA (mtDNA) damage contributed to increased oxidative stress, mitochondrial dysfunction and chondrocyte apoptosis.
Methods: We investigate the expression of genes regulating cholesterol efflux (NR1H3 and ABCA1) and influx (SREBF-2 and NPC1L1) in human chondrocytes that were isolated and graded according to the disease severity from the patients who were undergoing knee replacement surgeries. The effect of mtDNA damage on the mRNA expression of respiratory chain subunits, change of mitochondrial membrane potential (Δψm), overproduction of ROS, and apoptosis were assessed in high cholesterol-treated ACCs by qRT-PCR, flow cytometry, and confocal microscopy. The effects of high cholesterol treatment on the human and bovine cartilage explants were assessed by proteoglycan synthesis and various biochemical assays.
Results: In OA ACCs intracellular levels of cholesterol were higher compared to control group. Furthermore, OA ACCs showed dysregulation of the balance between cholesterol influx and efflux genes. Expression of cholesterol influx genes (SREBF-2 and NPC1L1) were increased in OA ACCs compared to control group. On the other hand, expression of cholesterol efflux genes, ABCA1 and NR1H3 were decreased in OA ACCs (Figure 1A). We then demonstrated that mtDNA oxidative damage increased rapidly after high cholesterol (300μM). Accordingly, treatment with high cholesterol resulted in decreased membrane potential and overproduction of ROS in ACCs (P < 0.05) and apoptosis (Figure 1B). Interestingly, cholesterol (300μM) treatment of cartilage explants culture showed an extensive proteoglycan loss (Figure 1C). MTT analysis showed that metabolic activity of ACCs was gradually decreased with ascending dose of cholesterol (50, 300, 600μM) stimulation. Protein and mRNA expression level of MMP-13 were increased in cholesterol-stimulated group compared to control; however, COL2A1 showed different expression trend after cholesterol treatment. Both protein and mRNA expression level of COL2A1 were increased in treatment group compared to control (Figure 1C).
Conclusion: mtDNA oxidative damage seems to be the “trigger” for cell dysfunction in high cholesterol-challenged ACCs by setting in motion the vicious circle of mtDNA damage leading to ROS overproduction and further apoptosis resulting in the development of abnormalities that resemble characteristic features associated with OA.