CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL‐medicated osteoclastogenesis: Evidence of NF‐κB–dependent, CD40‐mediated bone destruction in rheumatoid arthritis
Open Access
- 30 May 2006
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatism
- Vol. 54 (6), 1747-1758
- https://doi.org/10.1002/art.21873
Abstract
Objective To determine whether CD40 ligation of rheumatoid arthritis synovial fibroblasts (RASFs) is able to induce RANKL expression and osteoclastogenesis in RASFs, and to identify its mechanism of action in patients with RA. Methods CD40 of RASFs was ligated with CD40 ligand (CD40L)–transfected L cells or activated T cells. The formation of osteoclasts in cocultures of CD40-ligated RASFs and T lymphocyte–depleted peripheral blood mononuclear cells was evaluated by tartrate-resistant acid phosphatase staining, detection of calcitonin receptor, and resorption pit formation assay. The expression of NF-κB, IκBα, ERK-1/2, phospho-ERK-1/2, p38, phospho-p38, and RANKL was examined by immunoblotting and/or semiquantitative reverse transcription–polymerase chain reaction. Results CD40 ligation of RASFs by CD40L-transfected L cells or activated T cells induced RANKL expression and enhanced osteoclastogenesis. CD40 ligation of RASFs also induced activation of ERK-1/2, p38 MAPK, and NF-κB and up-regulation of CD40 ligation–induced RANKL expression, whereas osteoclastogenesis was reduced in RASFs transfected with a dominant-negative mutant of IκBα or by an NF-κB inhibitor. However, specific inhibitors of MAPK/ERK-1/2 and p38 MAPK partially blocked the induction of RANKL expression and osteoclastogenesis. Monoclonal antibodies against interleukin-1 and tumor necrosis factor α partially inhibited CD40 ligation–mediated osteoclastogenesis. Conclusion These results indicate that CD40 ligation of RASFs induces RANKL expression mainly via NF-κB activation and also results in enhanced osteoclast formation, both of which might play important roles in bone and cartilage destruction in RA. Inhibition of the CD40–CD40L interaction is a potential strategy for the prevention of bone damage in RA.Keywords
This publication has 45 references indexed in Scilit:
- Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblastsArthritis & Rheumatism, 2004
- NF-κB-dependent lymphocyte hyperadhesiveness to synovial fibroblasts by hypoxia and reoxygenation: potential role in rheumatoid arthritisJournal of Leukocyte Biology, 2003
- High levels of osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in serum of rheumatoid arthritis patients and their normalization after anti–tumor necrosis factor α treatmentArthritis & Rheumatism, 2002
- Inhibitor of nuclear factor ?B kinase ? is a key regulator of synovial inflammationArthritis & Rheumatism, 2001
- Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritisArthritis & Rheumatism, 2000
- A New Mechanism of Bone Destruction in Rheumatoid Arthritis: Synovial Fibroblasts Induce OsteoclastogenesisBiochemical and Biophysical Research Communications, 1997
- The many roles of CD40 in cell-mediated inflammatory responsesImmunology Today, 1996
- The importance of the t cell in initiating and maintaining the chronic synovitis of rheumatoid arthritisArthritis & Rheumatism, 1992
- The american rheumatism association 1987 revised criteria for the classification of rheumatoid arthritisArthritis & Rheumatism, 1988
- Identification of Three Major Synovial Lining Cell Populations by Monoclonal Antibodies Directed to Ia Antigens and Antigens Associated with Monocytes/Macrophages and FibroblastsScandinavian Journal of Immunology, 1983