Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Bavaria, Germany.
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.
Ann Rheum Dis. 2015 Feb;74(2):444-51. doi: 10.1136/annrheumdis-2013-203925. Epub 2013 Dec 2.
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.
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).
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.
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.
类风湿关节炎（RA）、骨关节炎（OA）和关节炎小鼠的研究表明，关节炎滑膜中有酪氨酸羟化酶阳性（TH(+)）细胞，且交感神经纤维平行缺失。TH(+)细胞的确切功能和 TH 诱导方式尚不清楚。
在常氧/缺氧条件下，用/不用 TH 的酶辅因子和 TH 抑制剂培养 RA/OA 的滑膜细胞。我们研究了 TH 表达和细胞因子/儿茶酚胺的释放。通过将 TH(+)神经前体细胞（TH(+)神经细胞）进行细胞治疗，在胶原 II 诱导的关节炎（CIA）的 DBA/1 小鼠中测试了体内功能。
与常氧条件相比，缺氧增加了 OA/RA 滑膜细胞中 TH 蛋白表达和儿茶酚胺合成，并减少了肿瘤坏死因子（TNF）的释放。用α-甲基-para-酪氨酸（αMPT）抑制 TH 可逆转这种对 TNF 的抑制作用，在缺氧条件下尤为明显。用特定的 TH 辅因子（四氢生物蝶呤和 Fe(2+)）孵育可增加缺氧诱导的 TNF 抑制，αMPT 也可逆转这种抑制。为了研究 TH(+)细胞的可能临床作用，我们从间充质干细胞中生成了鼠 TH(+)神经元细胞。TH(+)神经元细胞表现出典型的儿茶酚胺能表型。过继转移 TH(+)神经元细胞可显著减轻 CIA 小鼠的病情，而耗竭 TH(+)细胞的 6-羟多巴胺则逆转了这一作用。
首次提出了 TH(+)神经元细胞对实验性关节炎的抗炎作用。在 RA/OA 中，TH(+)滑膜细胞具有 TH 依赖性抗炎能力，在缺氧条件下增强。利用生成的 TH(+)神经元细胞可能为细胞治疗开辟新途径。
