Drs. H.-R. Kim and K.-W. Kim contributed equally to this work.
Reciprocal Activation of CD4+ T Cells and Synovial Fibroblasts by Stromal Cell–Derived Factor 1 Promotes RANKL Expression and Osteoclastogenesis in Rheumatoid Arthritis
Version of Record online: 25 FEB 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 3, pages 538–548, March 2014
How to Cite
Kim, H.-R., Kim, K.-W., Kim, B.-M., Jung, H.-G., Cho, M.-L. and Lee, S.-H. (2014), Reciprocal Activation of CD4+ T Cells and Synovial Fibroblasts by Stromal Cell–Derived Factor 1 Promotes RANKL Expression and Osteoclastogenesis in Rheumatoid Arthritis. Arthritis & Rheumatology, 66: 538–548. doi: 10.1002/art.38286
- Issue online: 25 FEB 2014
- Version of Record online: 25 FEB 2014
- Accepted manuscript online: 18 NOV 2013 11:22AM EST
- Manuscript Accepted: 14 NOV 2013
- Manuscript Received: 6 NOV 2012
- Basic Science Research Program through the National Research Foundation of Korea. Grant Numbers: NRF-2011-R1A4A007-0026961, NRF-2011-R1A4A002-0004723
- South Korea Ministry of Education, Science, and Technology
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.
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.
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.
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.