Decanoic acid reduces extracellular prostaglandin accumulation, inhibits MRP4 transport, and enhances low-dose dexamethasone effects in IL-1β-stimulated human osteoarthritis synoviocytes
Year: 2026
Type: article
Abstract: Objective: Persistent extracellular prostaglandin signaling contributes to synovial inflammation and pain in osteoarthritis (OA), although prostaglandin E2 (PGE2) can also have context-dependent homeostatic functions. Decanoic acid (DA) is a 10-carbon medium-chain fatty acid with reported peroxisome proliferator-activated receptor-modulating and anti-inflammatory activity. Its amphipathic carboxylate structure also made it an exploratory candidate for interaction with the hydrophobic organic-anion binding region of multidrug resistance protein 4 (MRP4/ABCC4). We tested whether DA changes prostaglandin compartmentalization and enhances the effect of very-low-dose dexamethasone (Dex) in interleukin-1β (IL-1β)-stimulated human OA fibroblast-like synoviocytes. Methods: Primary human osteoarthritis fibroblast-like synoviocytes were stimulated with IL-1β and treated with DA, Dex, or their combination. Extracellular and intracellular prostaglandins were quantified by competitive ELISA. MRP4 inhibition was evaluated in inside-out HEK293 membrane vesicles overexpressing human MRP4 using ATP-dependent DHEAS transport, with MK-571 as the positive inhibitor control. Molecular docking and UHPLC-MS lipidomics were also performed. Replicates were independently cultured wells or pellets from the same donor. Results: = 0.0402, indicating Das ability to potentiate the inhibitory effect of sub-nanomolar DEX. DA also reduced extracellular PGD2 and PGI2. In vesicles, DA inhibited MRP4-mediated DHEAS transport in a concentration-dependent manner (calculated IC50, approximately 33.86 μM), but PGE2 transport was not measured directly. Docking placed DA near the MK-571 reference pose. DA was also associated with increased 17(S)-HDHA and maresin 2 (MaR2). Conclusions: In this single-donor proof-of-concept model, DA altered prostaglandin distribution, inhibited MRP4 probe-substrate transport, and enhanced extracellular prostaglandin suppression in the presence of low-dose Dex. The findings are consistent with, but do not prove, an MRP4-associated contribution to prostaglandin export. The increases in 17(S)-HDHA and MaR2 are associative and do not establish that intracellular PGE2 retention caused resolution signaling. Multi-donor validation, direct PGE2 transport studies, genetic MRP4 experiments, and intra-articular pharmacokinetic and safety studies are required.
Source: Frontiers in Medicine
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223015369