The role of osteoprotegerin in arthritis
© BioMed Central Ltd 2003
Received: 1 July 2003
Accepted: 31 July 2003
Published: 8 August 2003
Bone erosion is a hallmark of rheumatoid arthritis. Recent evidence from experimental arthritis suggests that osteoclasts are essential for the formation of local bone erosions. Two essential regulators of osteoclastogenesis have recently been described: the receptor-activator of nuclear factor kappa B ligand, which promotes osteoclast maturation, and osteoprotegerin (OPG), which blocks osteoclastogenesis. The present review summarizes the current knowledge on the role of osteoclasts in local bone erosion. In addition, the role of OPG as a therapeutic tool to inhibit local bone erosion is addressed. Finally, evidence for OPG as an inhibitor of systemic inflammatory bone loss is discussed.
Keywordsbone erosion osteoclasts osteoporosis osteoprotegerin rheumatoid arthritis
Local bone erosions in rheumatoid arthritis
Rheumatoid arthritis (RA) is a highly osteodestructive process, which leads to local, juxta-articular and systemic bone loss. Local bone erosion is part of the classification criteria of RA, has become a key monitoring parameter of RA and is associated with unfavorable prognosis, such as functional loss [1–3].
From these histopathological observations it was evident that synovial inflammatory tissue has unique invasive properties, which even enable the invasion of bone and, finally, the destruction of bone. The molecular basis of this invasive nature has not been completely clarified and appears to be of a complex nature. Decreased apoptosis, activation of mitogenic signaling pathways and expression of enzymes that degrade the extracellular matrix, such as matrix metalloproteinases, play a part in this process [5–7]. Elegant studies have also linked such characteristics with synovial fibroblast-like cells of RA patients, which have intrinsic invasive properties and thus facilitate the spreading of inflammatory synovial tissue .
Evidence for a pivotal role of osteoclasts in local bone erosions
Bone erosion requires osteoclasts and, since the work of Bromley and Woolley, it has been known that inflammatory synovial tissue harbors osteoclasts . A detailed characterization of osteoclast precursors and mature osteoclasts within local bone erosions was then accomplished by Gravallese and colleagues in the late 1990s, demonstrating that cells in synovial pannus show all the different maturation steps of the osteoclast lineage . Furthermore, typical histological features of resorption lacunae were detected at the site of the erosion fronts. Lacunae are filled with multinucleated giant cells featuring typical morphological and molecular characteristics of mature osteoclasts.
Outcome of arthritis in osteoclast-free mouse models
Pettit et al. 
Redlich et al. 
K/BxN (serum transfer)
Mechanism of arthritis
Immune complex driven
Mechanism of bone pathology
Stromal cell defecta
Bone marrow cell defectb
Effect on inflammation
Effect on cartilage damage
Effect on bone erosion
Presence of osteoclasts
Further direct evidence for a pivotal role of osteoclasts in local bone erosion comes from c-fos knockout mice, which exhibit a maturation arrest of the osteoclast lineage without affecting differentiation of other hematopoetic cells or changing the properties of the stroma . These mice show complete uncoupling of synovial inflammation and bone erosion when arthritis is induced by overexpression of tumor necrosis factor (TNF) . The osteoclast thus emerges as an essential prerequisite to form erosive arthritis, and therefore appears an attractive therapeutic target for RA.
Concepts to inhibit osteoclasts in arthritis
Blockade of TNF-α and IL-1 are other currently used strategies. Both cytokines are potent osteoclastogenic factors, produced in inflammatory arthritis. Interestingly, clinical trials have shown that the effects of TNF-blockers on bone damage may exceed those effects on inflammation, suggesting that their ability to hamper osteoclast formation might be of important benefit [20, 21]. This is especially supported by the results from the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy, which showed that the effect of TNF-blockers on bone damage is independent of a clinical response to treatment . Other current experimental approaches such as the application of RGD peptides, of proton pump inhibitors, of matrix metalloproteinase inhibitors and also of blockers of mitogen-activated protein kinases/stress-activated protein kinases may add a future therapeutic repertoire to block osteoclasts.
Osteoprotegerin as inhibitor of osteoclastogenesis
Osteoprotegerin (OPG) has emerged as one of the most attractive tools to inhibit osteoclast formation during the past years. The interaction of RANKL with its receptor-activator of nuclear factor kappa B (RANK) is an essential signal for osteoclastogenesis [22–24]. Mice deficient for RANKL or RANK are osteopetrotic due to complete lack of osteoclasts [24, 25]. Thus, the interaction of RANKL, which is expressed by stromal cells and activated T cells, with RANK, found on osteoclast precursor cells and mature osteoclasts, is essential for osteoclastogenesis and osteoclast activation.
OPG functions as a naturally occurring decoy receptor of RANK and inhibits the RANKL/RANK interaction [26, 27]. Evidence that OPG has profound effects on bone comes from OPG knockout mice, which are osteoporotic due to deregulated RANKL/RANK interaction and increased osteoclast formation , and also comes from the administration of OPG to laboratory animals and humans, which leads to an increase of bone mass [28, 29]. The rationale for using OPG to inhibit the formation of local bone erosions in patients with RA comes from several observations: the presence of osteoclasts in local bone erosions as described earlier [9, 10], the increased expression of RANKL and RANK within synovial inflammatory tissue [30–32], and the fact that many proinflammatory mediators present in the synovial membrane, such as TNF, IL-1, IL-17 and prostaglandin E2, induce RANKL expression [33–35].
The effects of OPG on local bone erosion
Effects of osteoprotegerin in animal models of arthritis
Kong et al. 
Redlich et al. 
Romas et al. 
Onset of symptoms
Onset of symptoms
Onset of symptoms
Effect on inflammation
Effect on cartilage damage
Effect on bone erosion
Effect on osteoclast count
Effect on osteoporosis
These data suggest that, regardless of the nature of the precipitating mechanism, OPG appears a powerful tool to inhibit bone damage following synovial inflammation. Moreover, the RANKL/RANK interaction appears an important step in the formation of synovial osteoclasts, which is further supported by similar effects of other strategies to suppress RANKL expression, such as adeno-viral-based overexpression of IL-4, which is a potent antagonist of RANKL .
Systemic inflammatory bone loss and OPG
Apart from local bone erosion, systemic bone loss is a serious health burden in patients with RA. Osteoporosis develops in the majority of RA patients and is associated with increased fracture risk [39, 40]. Several factors precipitate systemic bone loss in RA patients, including female gender, high age, systemic use of glucocorticoids and decreased mobility of RA patients due to functional impairment. Interestingly, however, disease activity is also a major predictor for osteoporosis in RA patients, and is independent of other precipitating factors . This suggests that the inflammatory process not only affects local bone, but also leads to bone loss at distant sites, possibly due to a disturbed cytokine balance with a negative net effect on bone.
Open questions on OPG in arthritis
Currently, no data on the effects of OPG in human RA are available. Given the results from animal models of RA, the major role of OPG in human RA might be protection from local bone erosion and systemic bone loss. Whether bone can be protected more efficiently by OPG than by other strategies, such as anti-TNF, anti-IL-1 or potent bisphosphonates, remains to be determined.
In the TNF-transgenic model, OPG was equally potent to TNF-blockade in blocking local bone erosions, and was superior to the IL-1 receptor antagonist (unpublished observations). Recent data suggest that OPG treatment might exert some inhibitory effect on synovial inflammation, especially if combined with a TNF-blocker (unpublished observations). This may be explained by blockade of RANKL/RANK interactions other than those involved in osteoclastogenesis, such as the interaction of T cells with dendritic cells . Furthermore, binding of OPG to surface molecules distinct from RANKL, which has been demonstrated for tumor-necrosis-factor-related apoptosis inducing ligand, for example , could affect synovial inflammation. Also, the influence of OPG on loss of articular cartilage is controversial. Whereas protection of articular cartilage by OPG has been described in the adjuvant arthritis model , it is weak in the collagen-induced arthritis model  and is completely absent in the TNF-transgenic model . Expression of RANKL and RANK by chondrocytes has been described, but the function of these molecules in the cartilage is unknown . Thus, it is as yet unclear whether OPG affects cartilage destruction and synovial inflammation to a relevant degree, whereas the effect on bone is unequivocally proven.
There is a bulk of evidence that osteoclasts have a central role in local and systemic bone loss of inflammatory arthritis. Furthermore, pharmacological doses of OPG inhibit the formation of local bone erosions and restore normal bone mass in experimental models of arthritis. OPG thus appears a promising agent to block bone loss in RA. Since there is only a weak effect, if any, of OPG on inflammation, it is probable that its potential use in RA patients needs to be flanked by sufficient anti-inflammatory treatment. Patients with a high risk of bone loss might profit substantially from OPG, and it will be a challenge to select such patients by current clinical, laboratory and radiological assessments.
receptor-activator of nuclear factor kappa B
receptor-activator of nuclear factor kappa B ligand
tumor necrosis factor.
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