Activated human T cells directly induce osteoclastogenesis from human monocytes - Possible role of T cells in bone destruction in rheumatoid arthritis patients

Objective. To elucidate the direct role of human T cells in the induction o f osteoclastogenesis in rheumatoid arthritis (RA), by studying human monocy tes and the pathogenetic roles of receptor activator of nuclear factor kapp aB ligand (RANKL), RANK, and osteoprotegerin (OPG). Methods. Synovial tissue obtained at total knee replacement was stained imm unohistologically using anti-RANKL, CD3, and CD4 antibodies. Synovial fluid was obtained from patients with RA, osteoarthritis (OA), gout, or trauma. Concentrations of the soluble form of RANKL (sRANKL) and OPG in the synovia l fluid were measured by enzyme-linked immunosorbent assay. Activated T cel ls from peripheral blood mononuclear cells (PBMC) of healthy volunteers wer e cultured with human monocytes from PBMC. Results. Immunostaining of the synovial tissue of RA patients demonstrated that RANKL-positive cells were detected in a subset of fibroblast-like syno viocytes and infiltrating mononuclear cells. Double immunostaining revealed that RANKL-positive cells were detected in a subset of CD3+ cells and CD4 cells. An increased concentration of sRANKL and a decreased concentration of OPG were detected in synovial fluid from RA patients. The ratio of the c oncentration of sRANKL to that of OPG was significantly higher in synovial fluid of RA patients than in synovial fluid of patients with OA or gout. Th e activated T cells expressing RANKL induced osteoclastogenesis from autolo gous peripheral monocytes. The role of RANKL in this osteoclastogenetic pro cess was confirmed by dose-dependent inhibition by OPG. Conclusion. The present study is the first to demonstrate osteoclastogenesi s using human-derived T cells and monocytes. In addition, the present findi ngs suggest that excess production of RANKL by activated T cells increases the level of sRANKL in synovial fluid and may contribute to osteoclastic bo ne resorption in RA patients.