Background/Purpose:

Osteoarthritis (OA) is associated with a local inflammatory process. It is now considered as a metabolic syndrome rather than due to aging or mechanical stress. Several evidences point to the direction of an altered lipid metabolism as an underlying cause for the development of OA. Recently, we have studied the role played by an apolipoprotein, the acute phase serum amyloid A (A-SAA), as a pro-inflammatory marker in OA joints (de Seny et al., Plos One, 2013). Apolipoprotein A-I (ApoA1) is another major protein component of high-density lipoprotein (HDL) cargo molecules in plasma, and both are playing a major role in back cholesterol transport from peripheral tissues to the liver. 

Methods:

Lipoproteins, anti-oxidized LDL antibodies, cholesterol, ApoA1 levels and inflammatory parameters (IL-6, MMP-1 and MMP-3) in blood and synovial fluids of OA (n=29) and rheumatoid arthritis (RA) (n=27) patients were quantified and compared to those in matched healthy volunteers (HV) (n=35). Primary chondrocytes and fibroblast-like synoviocytes (FLS) were isolated respectively from cartilage and synovial membrane obtained from OA patients during joint replacement. Cells were stimulated with purified human ApoA1 in the presence or not of recombinant human A-SAA (rhSAA) protein, and with lipoproteins at physiological concentration encountered in OA. IL-6, MMP-1 and MMP-3 expression levels were quantified by ELISA after stimulation. 

Results:

1) In the serum of OA patients, LDL/HDL ratio was significantly higher compared to HV and RA but remained similar in both OA and RA synovial fluid.

2) Although LDL and cholesterol serum levels were higher in OA than in RA, both were lower in the OA synovial fluid than in the RA.

3) In the OA and RA synovial fluid, cholesterol levels were positively correlated to LDL, HDL and ApoA1 levels, and HDL levels were positively correlated to ApoA1 levels. But of interest, OA synovial fluid had the unique characteristic of LDL levels being positively correlated to HDL and ApoA1 levels, which was not observed neither in the synovial fluid of RA patients nor in the serum of OA, RA and HV.

4) LDL and ApoA1 levels were also significantly correlated to IL-6 levels, another uncommon characteristic of OA synovial fluid suggesting local dysregulated processes within lipidic and inflammatory parameters. We also observed using in vitro experiments that the purified human ApoA1 likewise rhSAA induced IL-6, MMP-1 and MMP-3 expression in primary chondrocytes and FLS obtained from OA patients. ApoA1-induced IL-6, MMP-1 and MMP-3 expression was downregulated by TAK242, a specific TLR4 inhibitor. Presence of HDL at OA physiological concentration did not abolished ApoA1-induced IL-6, MMP-1 and MMP-3 expression.

Conclusion:

Lipid diffusion into the joint cavity is dependent on the degree of inflammation. If inflammation is largely superior in RA compared to OA, we can nonetheless hypothesize that local inflammatory process and lipid diffusion inside OA joint cavity can also occur. In this study, several arguments have been raised in favour of an abnormal lipid profile in OA synovial fluid. This abnormal lipid profile was linked to the local pro-inflammatory process.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-lipid-metabolism-in-osteoarthritis-with-subsequent-proinflammatory-properties-of-apolipoprotein-a-i/