Background/Purpose:

Metabolic alterations take place in osteoarthritis (OA) and the mtDNA haplogorups influence the prevalence and severity of the disease. The aim of this work is to analyze the metabolic behavior in OA from different points of view, including the analysis of gene polymorphisms, mitochondrial variants and gene expression.

Methods:

The first approach consisted in the analysis of the influence of the mtDNA haplogroups in the body mass index (BMI) in a cohort of 638 OA patients and 474 healthy controls from Spain. This approach was followed by a second one that included the analysis of the expression levels of genes related to both lipid and glucose metabolism in RNA isolated from 24 OA and 22 healthy normal (N) cartilage samples; for this purpose we also used the chondrocyte cell line TC28a2 in order to analyse the glucose overload (at 1, 4.5 and 18 g/l) during 48 hours in the expression levels of these genes as well as of both MMP-3 and  IL-6; finally, we search for possible interactions between the mtDNA haplogroups and the SNP -866C/T (rs659366) in the promoter region of UCP2 to assess their incidence in the prevalence of OA in a cohort of 137 OA patients and 133 healthy controls from Spain. Nucleic acid isolation was carried out using commercial kits following the manufacturer recommendations with some modifications. Appropriate data analysis was performed with SPSS software (v19) and qBase plus software (Biogazelle).

Results: The mtDNA haplogroup J and OA are independently associated with BMI, so that carriers of this mitochondrial variant show significant lower BMI values (p=0.006) meanwhile OA patients show significant higher values (p<0.001), being the BMI a risk factor for OA.  The obtained OA/N expression ratio of GLUT1 (0.8±0.26), GLUT3 (0.73±0.01), GLUT5 (0.68±0.19), HK1 (1.09±0.02), HK2 (1.59±0.21), INSR (0.99±0.08), CPT1B (1.30±0.1), ACADM (2.65±0.36), HADHB (1.68±0.09), PPARg (0.61±0.11), PPARa (1.41±0.33) did not show significant differences (p > 0.05). However, a significant increased expression of UCP2 (3.86±0.12) as well as a decreased expression of PDK4 (0.20 ±0.01) was detected in OA cartilage samples (p<0.05). Gene expression of OLR-1 was only observed in OA cartilage samples. The experiments of glucose overload carried out in the cell line TC28a2 showed a direct correlation between glucose concentration and the expression levels of UCP2 (correlation coefficient (c.c)=0.965; p=0.102), MMP-3 (c.c=0.992; p=0.08) and IL-6 (c.c=0.996; p=0.05) as well as an inverse correlation with PDK4 (c.c= - 0.914; p=0.265). The analysis of the interaction between the mtDNA haplogroups and the SNP rs659366 showed that carriers of both haplogroups J or T (mtDNA cluster TJ) that also carry the T allele of rs659366 have a significant decreased risk of OA (OR=0.581; CI: 0.357 – 0.948; p=0.029).

Conclusion:

            This work provides strong evidence on metabolic alterations that occur in OA. These alterations involve the lipid and glucose metabolism, through the mitochondrial pathway, as well as the switch that modulates the balance between both metabolisms which, in turn, would lead to the increased inflammatory process that takes place in OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/new-insights-into-the-metabolic-origin-of-osteoarthritis/