Nerve growth factor: A key local regulator in the pathogenesis of inflammatory arthritis

Abstract Objective The effect of nerve growth factor (NGF) and its receptor (NGFR) in inflammatory diseases is a novel research field. The purpose of this study was to investigate the role of NGF/NGFR in human T cell subpopulations and fibroblast‐like synovial cells (FLS) and examine its pathophysiologic significance in psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Methods Expression of NGF/NGFR was examined in synovial fluid (SF), FLS, peripheral blood (PB)–derived T cells, and SF‐derived T cells from patients with PsA, RA, and osteoarthritis (OA). NGF levels were determined by enzyme‐linked immunosorbent assay. NGF‐induced T cell/FLS proliferation was examined by MTT assay. Low‐affinity (p75)/high‐affinity (TrkA) NGFR expression was determined by high‐dimensional fluorescence‐activated cell sorting. A monochlorobimane assay was used to determine the effect of NGF on T cell survival. Results Levels of NGF were higher in SF samples from PsA and RA patients as compared to SF samples from OA patients. NGF‐induced FLS proliferation was more marked in PsA and RA patients. TrkA was up‐regulated on activated SF T cells from PsA (mean ± SD 22 ± 6.2%) and RA (8 ± 1.3%) patients, whereas in SF samples from OA patients, TrkA+CD3+ T cells were not detectable. NGF induced the proliferation of PB T cells, induced the phosphorylation of Akt in activated T cells, and consistent with known pAkt activity, inhibited tumor necrosis factor α–induced cell death in these T cells. Conclusion Based on our findings, we propose a model in which NGF secreted by FLS into PsA and RA synovium promotes the survival of activated autoreactive T cells as well as FLS proliferation. Thus, NGF has the potential to sustain the chronic inflammatory cascades of arthritis of autoimmune origin.