The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models
✍ Scribed by Elena Neumann; Steffen Gay; Ulf Müller-Ladner
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 89 KB
- Volume
- 52
- Category
- Article
- ISSN
- 0004-3591
No coin nor oath required. For personal study only.
✦ Synopsis
Rheumatoid arthritis (RA) is characterized by inflammatory synovitis and progressive destruction of cartilage and bone. While the mechanisms of cartilage destruction in RA have been evaluated in detail, much less is known about destruction of articular bone. With regard to bone, there is evidence for an important role of osteoclasts in RA (1-3). In healthy individuals, bone remodeling is conducted by osteoblasts synthesizing bone matrix and its resorption by osteoclasts. Osteoblasts differentiate from mesenchymal stem cells, while osteoclasts originate from hematopoietic monocyte/ macrophage precursors (4-7). The receptor activator of NF-B (RANK)/RANKL system has been identified as an important factor in osteoclast cell differentiation and bone resorption (8-10). In addition, osteoprotegerin (OPG) functions as a high-affinity soluble decoy receptor for RANKL and competes with RANK for RANKL binding. Therefore, OPG is an effective inhibitor of the effects of RANK-RANKL interactions.
In recent years, numerous research groups have assessed the role of the RANK/RANKL/OPG system in RA. Several animal models have been used to study the in vivo effects of these 3 molecules in experimental arthritis. In this issue of Arthritis & Rheumatism, Wu et al (11) report on the role of RANKL in osteoclast formation in a new model of spontaneously developing erosive arthritis in the mouse. BXD2 mice, a recombinant inbred strain derived from C57BL/6 and DBA/2 mice, develop arthritis with bone erosions, synovial hyperplasia with mononuclear cell infiltration, and joint deformation; these features are observed at 6 months of age in 50% of female mice. In addition, these mice have high levels of rheumatoid factor and anti-DNA autoantibodies. Using this model, Wu and colleagues detected large numbers of osteoclasts in close proximity to macrophages and synovial fibroblasts next to sites of erosion. Moreover, they showed that synovial fibroblasts spontaneously and independently produced RANKL, inducing osteoclast formation by differentiation of bone marrowderived macrophages into osteoclasts by RANKL.
Similar to findings in other animal models of RA, inhibition of RANKL had no effects on inflammation but completely prevented bone loss and partially protected against cartilage loss in BXD2 mice (11). These findings are consistent with observations that inhibition of tumor necrosis factor (TNF) and interleukin-1 (IL-1) prevents inflammation and bone loss in human RA only to a limited extent (12-14), but inhibition of downstream RANKL effectors via OPG or other drugs could prevent bone destruction and reduce cartilage damage in human RA. On the other hand, systemic inhibition of RANKL may affect the functionality of the immune system. Since animal models are a key bridge between in vitro experiments and the development of new therapies including the manipulation of the RANK/RANKL/OPG system in RA, this new animal model of chronic RA could be an important tool for achieving this goal.
RANK/RANKL/OPG and bone resorption
RANKL. RANKL (also known as OPG ligand or osteoclast differentiation factor) is a membranespanning 38-kd protein that consists of 316 amino acids and belongs to the TNF superfamily. Three RANKL subunits form the functional molecule, which is anchored to the cell membrane and can be released from the cell after cleavage by the metalloproteinase disintegrin TNF␣ convertase (15,16). RANKL is highly expressed by osteoblasts, osteoclasts, endothelial cells, stromal cells, primitive mesenchymal cells surrounding the cartilage, and chondrocytes (8). Most important, it is