Metabolic Profiling Reveals Differences in Concentrations of Oxylipins and Fatty Acids Secreted by the Infrapatellar Fat Pad of Donors With End‐Stage Osteoarthritis and Normal Donors

Abstract

Objective. The infrapatellar fat pad (IPFP) in the knee joint is hypothesized to contribute to osteoarthritis (OA) development by the IFPF possibly by influencing inflammatory processes. Oxylipins are essential mediators in the inflammatory process. We undertook this study to investigate secretion by the IFPF of fatty acids and oxylipins derived from those fatty acids.Methods. IPFP explants from 13 OA donors undergoing joint replacement surgery and from 10 normal donors postmortem were cultured for 24 hours, and supernatants (fat-conditioned medium [FCM]) were collected. Liquid chromatography tandem mass spectrometry detected fatty acids and oxylipins in FCM samples. Univariate and multivariate (partial leastsquares discriminant analysis [PLS-DA]) analyses were performed, followed by pathway analysis. To validate these outcomes, a second set of OA FCM samples was measured (n ‫؍‬ 23).Results. Twenty-nine oxylipins and fatty acids could be detected in FCM. Univariate analysis showed no differences between normal donor and OA donor FCM; however, PLS-DA revealed an oxylipin/fatty acid profile consisting of 14 mediators associated with OA (accuracy rate 72%). The most important contributors to the model were lipoxin A 4 (decreased), thromboxane B 2 (increased), and arachidonic acid (increased). The statistical model predicted 64% of the second set of OA FCM samples correctly. Pathway analysis indicated differences in individual mediators rather than in complete pathways. Conclusion. The IPFP secretes multiple and different oxylipins, and a subset of these oxylipins provides a distinctive profile for OA donors. It is likely that the observed changes are regulated by the OA process rather than being a consequence of basal metabolism changes, as an increase in fatty acid levels was not necessarily associated with an increase in oxylipins derived from that fatty acid.

A longitudinal study of the association between infrapatellar fat pad maximal area and changes in knee symptoms and structure in older adults

“…In patients with OA, IPFP secretes higher levels of inflammatory cytokines and adipokines including interleukin 6, adipsin, adiponectin and visfatin than subcutaneous fat 20. It also generates multiple oxylipins, and patients with OA can be distinguished from normal donors based on the secretion of lipid mediators involved in the oxylipin pathways by IPFP 21. These suggest that inflamed IPFP may play a detrimental role in the pathogenesis of OA.…”

“…IPFP maximal area was associated with decreased IPFP abnormalities including signal intensity alteration (that may imply inflammation and oedema) and soft tissue thickening (that may represent fibrosis), indicating that IPFP size-related decreases in pathological changes of IPFP may play roles. It may also be that some biochemical factors secreted from IPFP are protective, because IPFP-derived fat-conditioned medium in healthy individuals contained elevated levels of anti-inflammatory lipid mediator lipoxin A4,21 and IPFP fat-conditioned medium of patients with OA inhibited catabolic processes in cartilage 28. Additionally, it may be due to the presence of mesenchymal stem cells (MSCs) in IPFP, since MSCs from IPFP had a higher chondrogenic and adipogenic capacity than MSCs from normal cartilage and bone marrow,29 and inhibited secretion of proinflammatory cytokines/chemokines from OA synovium and chondrocytes 30.…”

Omega-6 oxylipins generated by soluble epoxide hydrolase are associated with knee osteoarthritis

“…In a murine model of OA, serum levels of omega-6 PUFAs [arachidonic acid (AA), eicosadienoic acid, γ linoleic acid (LNA), and dihomo-γ-linolenic acid] correlated positively with OA, impaired healing, and inflammatory adipokines (6). In humans, a positive association between the plasma omega-6 PUFAs, AA, and synovitis has been reported (7) and increased levels of AA have been found in the infrapatellar fat in knee OA compared with controls (8). PUFAs derived either from omega-6 (LNA, dihomo-γ-linolenic acid, AA) or omega-3 PUFAs are substrates for a number of different enzymes that generate biologically active oxygenated metabolites known as oxylipins (9).…”

Responsiveness of Infrapatellar Fat Pad Volume Change to Body Weight Loss or Gain: Data from the Osteoarthritis Initiative

“…It may thus represent a source of intra-articular cytokine release (followed by inflammation and tissue degradation) (e.g. leptin secretion) and a potential link between obesity and knee OA [KleinWieringa et al, 2011;Hui et al, 2012;Conde et al, 2013a;Gierman et al, 2013].…”