gms | German Medical Science

Background: In recent studies catecholamines produced by tyrosine-hydroxylase-positive (TH+) synovial cells have been shown to mediate anti-inflammatory effects in vitro and in experimental arthritis [1]. TNF has been shown to be toxic to catecholaminergic neurons in Parkinson’s disease (PD) [2]. Therefore, the aim of this study was to analyze whether TNF exhibits also inhibitory effects on TH in the chronic inflamed synovium in rheumatoid arthritis (RA).

Methods: Human mixed synovial cells were isolated from RA and osteoarthritis (OA) patients and “induced TH+ cells” (iTH+) were generated from human mesenchymal stem cells (MSC) as described previously [1]. Cells were cultivated under hypoxia (1% O₂), because the microenvironment of inflamed joints is hypoxic. TNF and the anti-TNF etanercept were administered in different concentrations and combinations. Expression and activity of TH was analyzed by immunofluorescence and TH activity assay. Catecholamines were quantified via HPLC and the quality of catecholaminergic differentiation was investigated staining VMAT2, Nurr1, and βIII tubulin as markers. In addition, TNF toxicity was analyzed by LDH-assay.

Results: In mixed synovial cell culture, no significant effects of TNF on TH activity and catecholamine synthesis were observed. In general, TNF did not disturb catecholaminergic differentiation of MSCs to iTH+ cells. However, TH staining of TNF-treated iTH+ cells was weaker, the TH activity and the amount of produced catecholamines lower compared to untreated control in both OA and RA. Similarly, expression of VMAT2, Nurr1, and βIII tubulin decreased after TNF-treatment in iTH+ cells. The effects of TNF were reversed by etanercept in both iTH+ cell cultures. Cell viability was not affected by TNF.

Conclusion: This study shows TNF inhibition of TH expression and activity in iTH+ cells leading to the decrease of anti-inflammatory acting catecholamines. This might be a reason why newly appearing TH+ cells in the synovium are not able to unfold their anti-inflammatory effects in RA. This phenomenon was not confirmed in mixed synovial cell culture possibly due to preceding TNF-priming in the inflamed joint.