Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis

Abstract

Background: Inflammatory mediators in the synovial fluid (SF) play critical roles in the initiation and development of pain in knee osteoarthritis (KOA). However, data for inflammatory marker expression are conflicting, and the role of SF inflammatory mediators in neuropathic pain is not clear. Therefore, the aim of this study was to identify SF inflammatory mediators associated with nociceptive and neuropathic pain in KOA. Methods: Levels of IL-1β, IL-6, TNF-α, macrophage colony-stimulating factor, MMP-3, MMP-13, metalloproteinase with thrombospondin motifs 5, calcitonin gene-related peptide, neuropeptide Y, substance P and bradykinin were measured using enzyme-linked immunosorbent assays in 86 patients. Nociceptive pain was assessed using the numeric rating scale (NRS), visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. Neuropathic pain was determined using the PainDETECT questionnaire. Moreover, knee function was evaluated by the WOMAC score and range of motion (ROM) assessments. Radiological grade was defined using the Kellgren-Lawrence (K-L) grading scale. Results: Pain scores measured using different methods correlated highly with each other. A worse K-L grade and knee function were associated with worse pain. Expression of IL-1β and IL-6 was increased in the early stage compared with the late stage. The NRS score correlated positively with age, K-L grade, and the WOMAC score and negatively with ROM and TNF-α expression. The VAS correlated positively with age, K-L grade, and the WOMAC score but negatively with ROM and levels of IL-1β, IL-6 and TNF-α. The WOMAC pain score did not correlate with any of the inflammatory mediators measured; it correlated only with ROM. The PainDETECT score correlated only with the WOMAC score. Expression of other inflammatory mediators did not correlate with any of the pain scores. Conclusions: IL-1β, IL-6 and TNF-α play critical roles in pain in the early stage of KOA and correlate with pain. The catabolic enzymes and neuropeptides measured do not correlate with nociceptive and neuropathic pain. New biomarkers related to pain in the late stage need to be further investigated.

Development of Postoperative Pain in Patients with End-Stage Knee Osteoarthritis Is Associated with Upregulation of Genes Related to Extracellular Matrix Degradation, Inflammation, and Apoptosis Measured in the Peripheral Blood before Knee Surgery

“…Our results are in line with previous observations stating that increased concentrations of cytokines in the synovial fluid both correlated with pain in the early stages of OA [ 33 ] and were independent predictors of lesser pain improvement after knee surgery [ 20 ]. However, we noted that not every cytokine gene expression could serve as a pain prognostic marker, as in the examined OA patient cohort COX-2 baseline gene expression did not significantly differ between both subsets.…”

EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis

“…This reduction of pain may be correlated to the EPZ-6438 induced-downregulation of inflammatory markers, in particular PGE2 or IL-6, which are known to play a role in pain during osteoarthritis process 23 . PGE2 for instance is the best known lipid mediator that contributes to inflammatory pain in arthritic conditions 24,25 , while IL-6 is also associated with hyperalgesia and hypersensitivity in joint tissues 26 and play a critical role in pain at least in the early stage of knee osteoarthritis OA 27 . In the present study, we also demonstrate that EZH2 regulates NGF expression in chondrocytes, and that the inhibition of EZH2 reduces NGF expression.…”

Pain Characteristics and Biomarkers in Treatment Approaches for Osteoarthritis Pain

“…These markers are not specific to OA pain -indeed many, such as adhesion molecules, growth factors and matrix proteins, have roles in tissue growth and turnover [62] and others are involved in inflammation and pain more generally (TNFα, IL-1β) [15]. However, their levels have been shown to vary significantly with severity of OA pain: Increasing levels of inflammatory markers and other cytokines, markers for cartilage and bone turnover, growth factors and adhesion molecules were associated with more severe pain scale scores [56][57][58][59][61][62][63][64][65][66][67][68], as were decreasing levels of IL-1β and macrophage-derived chemokine [59,61]. Both positive [56,59] and negative [61] associations with pain severity have been reported for TNF-α and IL-6.…”

“…However, their levels have been shown to vary significantly with severity of OA pain: Increasing levels of inflammatory markers and other cytokines, markers for cartilage and bone turnover, growth factors and adhesion molecules were associated with more severe pain scale scores [56][57][58][59][61][62][63][64][65][66][67][68], as were decreasing levels of IL-1β and macrophage-derived chemokine [59,61]. Both positive [56,59] and negative [61] associations with pain severity have been reported for TNF-α and IL-6. Levels of biomarkers also vary with OA progression as measured by K-L staging: in multiple studies [58,62,[67][68][69][70][71][72][73], inflammatory markers and other cytokines, growth factors, adhesion molecules and markers for cartilage and bone turnover increased with K-L stage (Table 1).…”