The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages

Abstract

Our objective was to investigate sym‐pathetic and sensory nerve fibers in synovial tissue in rheumatoid arthritis (RA) and osteoarthritis (OA) in relation to histological inflammation and synovial cytokine and norepinephrine (NE) secretion. Immu‐nohistochemistry was used to detect nerve fibers and inflammatory parameters. A superfusion technique of synovial tissue pieces was used to investigate cytokine and NE secretion. In RA, we detected 0.2 ± 0.04 tyrosine hydroxylase‐positive (TH‐positive=sympathetic) nerve fibers/mm 2 as com‐pared to 4.4 ± 0.8 nerve fibers/mm 2 in OA ( P <0.001). In RA, there was a negative correlation between the number of TH‐positive nerve fibers and inflammation index (R Rank =−0.705, P =0.002) and synovial secretion (R Rank =−0.630, P =0.009), which was not found in OA. Substance P‐positive (=sensory) nerve fibers were increased in RA as compared to OA (3.5 ±0.2 vs. 2.3±0.3/mm 2 , P =0.009). Despite lower numbers of sympathetic nerve fibers in RA than in OA, NE release was similar at baseline (RA vs. OA: 152±36 vs. 106±21 pg/ml, n.s.). Basal synovial NE secretions correlate with the number of TH‐positive CD 163 + synovial macro‐phages (RA: R Rank =0.622, P =0.031; OA: R Rank = 0.299, n.s.), and synovial macrophages have been shown to produce NE in vitro . Whereas sympathetic innervation is reduced, sensory innervation is in‐creased in the synovium from patients with long‐standing RA when compared to the synovium from OA patients. The differential patterns of innervation are dependent on the severity of the inflammation. However, NE secretion from the synovial tissue is maintained by synovial macrophages. This demon‐strates a loss of the influence of the sympathetic nervous system on the inflammation, accompanied by an up‐regulation of the sensory inputs into the joint, which may contribute to the maintenance of the disease.—Miller, L. E., Jüsten, H.‐P., Schölmerich, J., Straub, R. H. The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages. FASEB J. 14, 2097–2107 (2000)