Apolipoprotein-A1 as a Damage-Associated Molecular Patterns Protein in Osteoarthritis: Ex Vivo and In Vitro Pro-Inflammatory Properties

Abstract

Osteoarthritis (OA) is associated with a local inflammatory process. Dyslipidemia is known to be an underlying cause for the development of OA. Therefore, lipid and inflammatory levels were quantified ex vivo in blood and synovial fluid of OA patients (n=29) and compared to those of rheumatoid arthritis (RA) patients (n=27) or healthy volunteers (HV) (n=35). The role of apolipoprotein A-I (ApoA1) was investigated in vitro on inflammatory parameters using human joint cells isolated from cartilage and synovial membrane obtained from OA patients after joint replacement. Cells were stimulated with ApoA1 in the presence or not of serum amyloid A (SAA) protein and/or lipoproteins (LDL and HDL) at physiological concentration observed in OA synovial fluid. In our ex vivo study, ApoA1, LDL-C and total cholesterol levels were strongly correlated to each other inside the OA joint cavity whereas same levels were not or weakly correlated to their corresponding serum levels. In OA synovial fluid, ApoA1 was not as strongly correlated to HDL as observed in OA serum or in RA synovial fluid, suggesting a dissociative level between ApoA1 and HDL in OA synovial fluid. In vitro, ApoA1 induced IL-6, MMP-1 and MMP-3 expression by primary chondrocytes and fibroblast-like synoviocytes through TLR4 receptor. HDL and LDL attenuated joint inflammatory response induced by ApoA1 and SAA in a ratio dependent manner. In conclusion, a dysregulated lipidic profile in the synovial fluid of OA patients was observed and was correlated with inflammatory parameters in the OA joint cavity. Pro-inflammatory properties of ApoA1 were confirmed in vitro.

Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis

“…After 24 h of starvation, cells were incubated with oxidized human LDL (h-oxLDL; 50 μg·mL À1 ) or with a pool of serum from the control group of our rabbit model (4% HFD serum) for 24 h to become foam cells. The final amount of TC and LDL in the cell culture was in the same range as those expected in the synovial fluid of RA patients (65 mg·mL À1 of TC and 60 mg·mL À1 of LDL) (Oliviero et al, 2009;Oliviero et al, 2012;De Seny et al, 2015). Cells were then stimulated for 24 h with recombinant human IFNγ (50 ng·mL À1 ) in presence or absence of tofacitinib dissolved in DMSO at different doses (CP-690550; Pfizer International, Peapack, NJ, USA).…”

Cholesterol metabolism in pathogenesis of osteoarthritis disease

“…Supporting this notion, a study has shown that synovial fluid of OA patients showed dysregulated lipid profile and correlated with inflammatory parameters in the OA joint cavity. The same authors demonstrated that APOA‐1 expression as well as HDL and LDL concentrations would influence the inflammatory properties of cholesterol regulating gene APOA‐1 in chondrocytes and fibroblast‐like synoviocytes . Another study has demonstrated that sterol regulatory element binding proteins (SREBPs), a key transcription factor regulating cholesterol metabolism, is involved in OA pathogenesis .…”

“…The same authors demonstrated that APOA-1 expression as well as HDL and LDL concentrations would influence the inflammatory properties of cholesterol regulating gene APOA-1 in chondrocytes and fibroblast-like synoviocytes. 48 Another study has demonstrated that sterol regulatory element binding proteins (SREBPs), a key transcription factor regulating cholesterol metabolism, is involved in OA pathogenesis. 17 In a recent study, importance of hedgehog signaling in chondrocytes has been demonstrated in regulating cholesterol homeostasis.…”

Electroacupuncture Prevents Osteoarthritis of High‐Fat Diet‐Induced Obese Rats

“…Obesity-related hyperlipemia is characterized by low systemic levels of high-density lipoprotein (HDL) and high levels of total cholesterol (TC), triglyceride (TG), and oxidized low-density lipoprotein (ox-LDL) [ 9 ]. Previous studies have pointed out that high serum TC and TG levels and lack of HDL have been linked to progression of cartilage loss in knee OA [ 10 , 11 ]. In particular, lack of HDL predisposes mice to osteoarthritis following long-term exposure to high-fat diet (HFD) [ 12 ].…”