Reciprocal Activation of CD4+ T Cells and Synovial Fibroblasts by Stromal Cell–Derived Factor 1 Promotes RANKL Expression and Osteoclastogenesis in Rheumatoid Arthritis

Objective Stromal cell–derived factor 1 (SDF‐1) is a chemokine that is involved in the bone‐destructive process in rheumatoid arthritis (RA) and bony metastasis in malignancy. This study was undertaken to determine the role and mechanism of SDF‐1 in RA‐associated osteoclastogenesis. Methods The expression of SDF‐1, tumor necrosis factor α (TNFα), and RANKL in RA synovial tissue was analyzed using confocal microscopy. After synovial fibroblasts and CD4+ T cells were treated with SDF‐1, RANKL messenger RNA expression was determined by real‐time and reverse transcription polymerase chain reaction. Osteoclastogenesis was assessed by counting tartrate‐resistant acid phosphatase–positive multinucleated cells in CD14+ monocytes cultured with SDF‐1 in the presence of anticytokine antibodies or signal inhibitors and in monocytes cocultured with SDF‐1–pretreated synovial fibroblasts and CD4+ T cells. Results RANKL, TNFα, and SDF‐1 were coexpressed in the lining and sublining of RA synovium. SDF‐1 stimulated RANKL expression in RA synovial fibroblasts and CD4+ T cells, and TNFα inhibition reduced this stimulation. When monocytes isolated from human peripheral blood were cultured with SDF‐1, they were differentiated into osteoclasts in the absence of RANKL. Monocytes were also differentiated into osteoclasts when they were cocultured with SDF‐1–pretreated synovial fibroblasts or CD4+T cells; however, this osteoclastogenesis was reduced by TNFα inhibition. Conclusion Our findings indicate that SDF‐1 induces osteoclastogenesis directly and indirectly via up‐regulating RANKL expression in RA synovial fibroblasts and CD4+ T cells, and that this is mediated by TNFα. The axis of SDF‐1 and RANKL is a potential therapeutic target for RA‐associated bone destruction.