The regulatory role of nerve growth factor and its receptor system in fibroblast-like synovial cells

Objectives: Investigating the role of nerve growth factor (NGF) and its receptors (NGF-R) in inflammatory diseases is an active field of research. Inflammatory diseases of the joint are the commonest cause of human morbidity but very little is known about the effect of NGF on synovial tissue biology. Here we have studied NGF/NGF-R and their functional significance on cultured fibroblast-like synovial cells (FLS) collected from the synovial tissue of five healthy subjects. Methods: NGF/NGF-R expression was determined in the basal condition and after stimulation with tumour necrosis factor (TNF) and interleukin (IL)-1 by enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS). Proliferation studies were performed by cell count, hexosaminidase assay, and the MTT assay. The synovial fluid (SF) NGF level was studied by ELISA in 12 psoriatic arthritis (PsA), 14 rheumatoid arthritis (RA), and 10 osteoarthritis (OA) patients. Results: FACS studies showed that unstimulated FLS expressed low levels of NGF and the high-affinity NGF-tyrosine kinase receptor TrkA, and TNF and IL-1 increased NGF and TrkA expression in FLS. NGF (100 ng/mL) increased FLS proliferation by 400% compared to the control (medium only). The NGF level was significantly higher in the PsA group (365.585.2 pg/mL) than in the RA (12035 pg/mL) and OA groups (306 pg/mL). Conclusions: Upregulation of NGF/TrkA in proinflammatory cytokine-activated FLS, the mitogenic effect of NGF on FLS, and the increased NGF level in SF of inflammatory arthritis suggest that there is cross-talk between NGF/NGF-R and FLS. These results also suggest that dysregulated production of NGF may lead to synovial cell proliferation and thus could influence the inflammatory and proliferative cascades of inflammatory arthritis.