High levels of TDO2 in relation to pro-inflammatory cytokines in synovium and synovial fluid of patients with osteoarthritis

Abstract

Background Tryptophan 2,3-dioxygenase (TDO2) is the primary enzyme that catabolizes tryptophan to kynurenine. Numerous studies have suggested that TDO2 is involved in inflammation-related diseases. However, its role in osteoarthritis (OA) has not yet been investigated. The aim of the present study was to explore the levels of TDO2 in the synovium and synovial fluid (SF) of patients with OA and its correlation with clinical manifestations and levels of pro-inflammatory cytokines. Methods Synovium and SF samples were collected from patients with OA and patients with joint trauma (controls) during surgery. An enzyme-linked immunosorbent assay (ELISA) was used to measure TDO2, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in the synovium and SF. Diagnostic performance of TDO2 in the synovium to discriminate between controls and OA patients was assessed using receiver operating characteristic (ROC) curve analysis. Correlations between TDO2 levels, OA clinical features, and pro-inflammatory cytokines were evaluated using Pearson correlation analysis. Effects of IL-1β or TNF-α stimulation on TDO2 expression in OA-fibroblast-like synoviocytes (OA-FLS) were also examined. Results The levels of TDO2, IL-1β, and TNF-α in the synovium of patients with OA were found to be significantly higher than those in controls. ROC curve analysis revealed an area under the curve (AUC) of 0.800 with 64.3% sensitivity and 85.0% specificity of TOD2 in the synovium, which enabled discriminating patients with OA from controls. Moreover, protein expression of TDO2 was upregulated to a greater extent in OA-FLS than in normal synovial fibroblasts (NSF). Furthermore, the levels of TDO2 showed significantly positive correlation with IL-1β and TNF-α levels in the synovium and SF. TDO2 levels in the synovium were also positively correlated with the Kellgren-Lawrence score. Additionally, TDO2 protein expression was significantly increased in IL-1β‒ or TNF-α‒stimulated OA-FLS than in control FLS. Conclusion These data indicate that highTDO2 levels in the synovium can be correlated with pro-inflammatory cytokines and severity of OA.

Identification of biomarkers related to tryptophan metabolism in osteoarthritis

“…Studies have shown that the level of TDO2 in patients with OA was remarkably higher than these without arthritis. Further analysis found that the level of TDO2 in knee joint synovial membrane and synovial fluid of OA patients was positively correlated with clinical manifestations, KL grade and proinflammatory cytokine levels [ 22 ]. Recently, the expression of TDO2 has been reported to be highly upregulated in joint tissues of rheumatoid arthritis patients and rats with help-induced arthritis [ 23 ].…”

Protective effects of Typhonii Rhizoma in rheumatoid arthritis rats revealed by integrated metabolomics and network pharmacology

“…In tryptophan metabolism, a variety of enzymes such as indoleamine 2,3‐dioxygenase 1 (IDO1), indoleamine 2,3‐dioxygenase 2 (IDO2) and tryptophan‐2,3‐dioxygenase (TDO2) were associated with inflammatory processes (Orabona et al, 2008). TDO2 could trigger the proliferation and migration of fibroblasts and result in joint destruction (Rong et al, 2022). A major metabolite, 5‐hydroxytryptamine (5‐HT), had been shown to activate multiple immune cells when combined with 5‐HT receptors (5‐HTRs), and a deficiency of 5‐HT has been related to the formation and activation of osteoclasts in RA (Chabbi‐Achengli et al, 2016).…”

“…TDO2 could trigger the proliferation and migration of fibroblasts and result in joint destruction (Rong et al, 2022). A major metabolite, 5-hydroxytryptamine (5-HT), had been shown to activate multiple immune cells when combined with 5-HT receptors (5-HTRs), and a deficiency of 5-HT has been related to the formation and activation of osteoclasts in RA (Chabbi-Achengli et al, 2016).…”

Immune-related genes probably increase the occurrence of Interstitial Lung Disease in Dermatomyositis

“…However, in other diseases, such as hepatocellular carcinoma, it has been found that TDO2 expression contributes to the secretion of interleukin-6 (IL-6), which promotes tumour cell proliferation through STAT3 and NF-kB/TIM4 signalling [29]. In osteoarthritis patients, TDO2 levels were signi cantly and positively correlated with IL-1β and TNF-α levels, suggesting that high levels of TDO2 in the synovium may correlate with pro-in ammatory cytokines and the severity of osteoarthritis [30]. Among these, IL-6 plays a vital role in the in ammatory process, and studies have found higher levels of IL-6 in DM patients than in healthy populations [31].…”