Objectives Studies in rheumatoid arthritis (RA), osteoarthritis (OA) and mice with arthritis demonstrated tyrosine hydroxylase-positive (TH⁺) cells in arthritic synovium and parallel loss of sympathetic nerve fibres. The exact function of TH⁺ cells and mode of TH induction are not known.

Methods Synovial cells of RA/OA were isolated and cultured under normoxic/hypoxic conditions with/without stimulating enzyme cofactors of TH and inhibitors of TH. We studied TH expression and release of cytokines/catecholamines. In vivo function was tested by cell therapy with TH⁺ neuronal precursor cells (TH⁺ neuronal cells) in DBA/1 mice with collagen type II-induced arthritis (CIA).

Results Compared with normoxic conditions, hypoxia increased TH protein expression and catecholamine synthesis and decreased release of tumour necrosis factor (TNF) in OA/RA synovial cells. This inhibitory effect on TNF was reversed by TH inhibition with α-methyl-para-tyrosine (αMPT), which was particularly evident under hypoxic conditions. Incubation with specific TH cofactors (tetrahydrobiopterin and Fe²⁺) increased hypoxia-induced inhibition of TNF, which was also reversed by αMPT. To address a possible clinical role of TH⁺ cells, murine TH⁺ neuronal cells were generated from mesenchymal stem cells. TH⁺ neuronal cells exhibited a typical catecholaminergic phenotype. Adoptive transfer of TH⁺ neuronal cells markedly reduced CIA in mice, and 6-hydroxydopamine, which depletes TH⁺ cells, reversed this effect.

Conclusions The anti-inflammatory effect of TH⁺ neuronal cells on experimental arthritis has been presented for the first time. In RA/OA, TH⁺ synovial cells have TH-dependent anti-inflammatory capacities, which are augmented under hypoxia. Using generated TH⁺ neuronal cells might open new avenues for cell-based therapy.