title: Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecholaminergic cells in experimental arthritis.
abstract: OBJECTIVE
  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 Fe(2+)) 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.
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Jenei-Lanzl
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Bavaria, Germany Division of Endocrinology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Capellino
authors.affiliation: Department of Pharmacology and Toxicology, University Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Frieder
authors.initials: F
authors.lastname: Kees
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fleck
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Lowin
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002395:Catecholamines / Q000378:metabolism; D017690:Cell Transplantation / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D051379:Mice; D008811:Mice, Inbred DBA; D058953:Neural Stem Cells / Q000637:transplantation*; D010003:Osteoarthritis / Q000473:pathology*; D013583:Synovial Membrane / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002395:Catecholamines; D014446:Tyrosine 3-Monooxygenase
keywords: Arthritis; Inflammation; Treatment