Increased prevalence of semaphorin 3C, a repellent of sympathetic nerve fibers, in the synovial tissue of patients with rheumatoid arthritis

Arthritis Rheum. 2004 Apr;50(4):1156-63. doi: 10.1002/art.20110.


Objective: The presence of selective sympathetic nerve repellents, i.e., semaphorins, may be responsible for the observed reduction of sympathetic innervation in the synovial tissue of patients with rheumatoid arthritis (RA). This study was undertaken to investigate the presence of different semaphorins in synovial tissue of patients with RA, patients with osteoarthritis (OA), and control subjects without inflammation.

Methods: In situ hybridizations with digoxigenin-labeled RNA probes directed against different semaphorins were performed. The presence of semaphorin 3C (S3C) in the synovial tissue of 10 RA, 10 OA, and 5 control subjects was investigated using a polyclonal antiserum directed against S3C.

Results: All in situ hybridizations revealed the presence of S3C messenger RNA, but no other investigated semaphorin (i.e., against primary afferent sensory nerve fibers), in the synovial tissue of RA and OA patients. Immunohistologic double staining demonstrated that macrophages and fibroblasts were positive for S3C protein. Quantitative analysis of S3C protein staining showed an increased density of S3C-positive cells in the synovial tissue of RA patients (mean +/- SEM 339 +/- 65 cells/mm(2)) in comparison with OA patients (168 +/- 27/mm(2); P = 0.031 versus RA) and controls (126 +/- 26/mm(2); P = 0.027 versus RA). Studies of the relationship between sympathetic nerve fiber density and S3C-positive cell density in the tissue of all patients showed that RA patients generally had lower densities of sympathetic nerve fibers and higher densities of S3C-positive cells than OA patients and control subjects.

Conclusion: These findings suggest that S3C from macrophages and fibroblasts, which is selectively directed against sympathetic nerve fibers, could be one element responsible for reduced sympathetic innervation in RA tissue. The inability of sympathetic nerve fibers to reinnervate synovial tissue could contribute to the chronic nature of RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Fibers / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Arthritis, Rheumatoid / physiopathology*
  • Biomarkers
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Female
  • Humans
  • In Situ Hybridization
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons, Afferent / metabolism
  • RNA, Messenger / analysis
  • Semaphorin-3A*
  • Solubility
  • Synovial Membrane / innervation*
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • Biomarkers
  • Carrier Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • SEMA3A protein, human
  • Semaphorin-3A