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

Abstract

ObjectiveThe 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.MethodsIn 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.ResultsAll 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/mm2) in comparison with OA patients (168 ± 27/mm2; P = 0.031 versus RA) and controls (126 ± 26/mm2; 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.ConclusionThese 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.

Marked loss of sympathetic nerve fibers in chronic Charcot foot of diabetic origin compared to ankle joint osteoarthritis

“…13 In the present study, we also demonstrated SEMA3C in Charcot foot, which was particularly present in cells of adjacent synovial tissue and bone.…”

“…Control stainings with preimmunization serum and with peptide-neutralized SEMA3C antibody solution were carried out in parallel. 13 These controls always yielded negative results.…”

“…13 Cryosections (5 mm) of at least two different formaldehyde-fixed tissue samples were air dried for 1 h and then rehydrated in 0.05 M TBS. Unspecific binding sites were blocked with 0.05 M TBS containing 10% fetal calf serum, 10% bovine serum albumin, and 10% normal chicken serum for 1 h at room temperature.…”

“…12 This diverging behavior of sympathetic versus sensory nerve fibers has been hypothesized to depend on the differential effects of nerve repellent factors. 13 This study aimed to determine the density of sympathetic and sensory SPþ nerve fibers in Charcot joints and, for comparison, in osteoarthritic joints at the same anatomical area (the tarsus). To give a complete picture of the nerve fiber density, the bone, the adjacent synovial tissue of affected joints, and the adjacent skin were investigated in the same patient.…”

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

“…In cohort 2 only, synovial tissue samples were obtained immediately after opening the knee joint capsule, preparation of which has been described previously (20). A piece of synovial tissue of up to 9 cm 2 was dissected.…”