Abstract
(1) Background: Synovial fluid (SF) from knee joints with osteoarthritis (OA) has increased levels of phospholipids (PL). We have reported earlier that TGF-ß and IGF-1 stimulate fibroblast-like synoviocytes (FLS) to synthesize increased amounts of PLs. The current study examined whether IL-1ß induces the release of PLs in FLS and the underlying mechanism. (2) Methods: Cultured human OA FLS were treated with IL-1ß alone and with pathway inhibitors or with synthetic liver X receptor (LXR) agonists. Cholesterol hydroxylases, ABC transporters, apolipoproteins (APO), LXR, sterol regulatory binding proteins (SREBPs), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were analyzed by RT-PCR, Western blot, and ELISA. The release of radiolabeled PLs from FLS was determined, and statistical analysis was performed using R (N = 5–9). (3) Results: Like synthetic LXR agonists, IL-1ß induced a 1.4-fold greater release of PLs from FLS. Simultaneously, IL-1ß upregulated the level of the PL transporter ABCA1 and of cholesterol hydroxylases CH25H and CYP7B1. IL-1ß and T0901317 stimulated the expression of SREBP1c, whereas only T0901317 enhanced SREBP2, HMGCR, APOE, LXRα, and ABCG1 additionally. (4) Conclusions: IL-1ß partially controls PL levels in OA-SF by affecting the release of PLs from FLS. Our data show that IL-1ß upregulates cholesterol hydroxylases and thus the formation of oxysterols, which, as natural agonists of LXR, increase the level of active ABCA1, in turn enhancing the release of PLs.
Highlights
The nearly frictionless motion of joints is enabled by a thin layer of complexed macromolecules that comprise phospholipids (PLs), hyaluronan, and lubricin, which coat the articulating surfaces and are replenished by synovial fluid (SF) [1]
Our data show that IL-1ß upregulates cholesterol hydroxylases and the formation of oxysterols, which, as natural agonists of liver X receptor (LXR), increase the level of active ABCA1, in turn enhancing the release of PLs
Using cultured human OA fibroblast-like synoviocytes (FLS) in a previous study, we showed that transforming growth factor-ß1 (TGF-ß1) and insulin-like growth factor-1 (IGF-1) stimulate the biosynthesis of the major PL phosphatidylcholine (PC), whereas interleukin-1ß (IL-1ß) enhances that of phosphatidylethanolamine and plasmalogens [6,7]
Summary
The nearly frictionless motion of joints is enabled by a thin layer of complexed macromolecules that comprise phospholipids (PLs), hyaluronan, and lubricin, which coat the articulating surfaces and are replenished by synovial fluid (SF) [1]. Human OA chondrocytes contain lipid droplets and express lower levels of LXRs, ABCA1, and APOA1 involved in cholesterol efflux [12,15]. Choi et al [22] reported that OA chondrocytes contain elevated levels of cholesterol due to augmented uptake and upregulation of CH25H and CYP7B1, increasing the content of oxysterols [23]. They showed that adenoviral overexpression of either hydroxylase causes OA in mice and that both hydroxylases are upregulated in human OA cartilage [22]. We found that the binding of agonists to LXR and the post-translational effects of IL-1ß enhance the expression of ABCA1 transporters, resulting in greater release of PLs from FLS. IL-1ß and LXRα Agonists Induce Greater Release of PLs from FLS
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