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The role of osteoprotegerin in arthritis
Arthritis Res Thervolume 5, Article number: 239 (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.
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].
The first scientific description of local bone erosion came from the Austrian pathologist Anton Weichselbaum , who termed such lesions as "caries of the joint ends" (Fig. 1). Indeed, bone is eroded eccentrically starting from the junction zone, where the bone, the cartilage and the synovial membrane are closely attached to each other (Fig. 2). Bone is invaded by an inflammatory synovial tissue, known as 'pannus', which contains fibroblasts, mononuclear infiltrates, mast cells and numerous blood vessels.
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.
These results have consequently lead to increasing interest in the role of osteoclasts in local bone erosion that is driven by the hypothesis that synovial pannus makes use of osteoclasts to accomplish bone damage. This assumption has now been supported by two studies that investigated the course of arthritis in genetically engineered mice, which lack osteoclasts (Table 1). Thus, while in wild-type mice the transfer of serum from arthritic K/BxN mice leads to immune complex-mediated, destructive synovitis, such serum transfer into receptor-activator of nuclear factor kappa B ligand (RANKL)-deficient mice leads to normal development of clinical arthritis, but the disease is not erosive . RANKL-deficient mice have defective osteoclastogenesis due to defective presentation of RANKL, an essential signal for osteoclastogenesis, to osteoclast precursors .
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
Inhibition of osteoclasts can be achieved by several different therapeutic strategies (Fig. 3). One of the best known and currently applied strategies are bisphosphonates, which inhibit osteoclasts through a complex mechanism including the inhibition of osteoclast attachment to the bone surface and the promotion of osteoclast apoptosis through inhibition of the mevalonate pathway. Based on the assumption that osteoclasts are essential for the formation of local bone erosion, bisphosphonates should inhibit this process. Indeed, pamidronate blocks local bone erosion in TNF-driven arthritis to a certain degree . Only a few clinical studies have yet addressed the efficacy of bisphosphonates to inhibit local bone erosions in RA, and the results are conflicting [16–19]. However, only bisphosphonates of low potency such as etidronate were studied, which may fail to accomplish full inhibition of osteoclasts in the lesions. New, more potent bisphosphonates may thus shed new light on the efficacy of bisphosphonates on local bone erosion.
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
The efficacy of OPG to block local bone erosions has now been documented in different experimental models of arthritis, supporting the idea that RANKL-induced osteoclastogenesis and osteoclast activation is a key determinant in the formation of local bone erosion [15, 36, 37] (Table 2).
OPG was first studied in adjuvant arthritis, based on the hypothesis that RANKL expression by activated T cells is involved in bone resorption in this T-cell-driven arthritis model . Indeed, OPG blocked bone erosion but did not affect synovial inflammation. Interestingly, OPG also affects bone erosion in a TNF-driven arthritis model, which is T-cell independent . In this model, OPG reduced or even blocked bone erosion but had no major effect on synovial inflammation, suggesting that blockade of osteoclast generation and function is the mechanism involved (Fig. 4). This is supported by the reduction of synovial osteoclasts by OPG. These data were finally confirmed by observations in the collagen-induced arthritis model, showing protection of bone upon OPG treatment while synovial inflammation was not affected .
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.
The fact that osteoporosis in RA patients is due to increased bone resorption fuels the concept that cytokines, which stimulate osteoclastogenesis, are overexpressed and lead to systemic osteoporosis in RA patients . This hypothesis is strongly supported by the fact that TNF-transgenic mice not only develop erosive arthritis, but are also severely osteoporotic . Since TNF is a potent cofactor in RANKL-mediated osteoclastogenesis, OPG appears a feasible tool to treat inflammatory bone loss. Indeed, treatment of OPG reverses osteoporosis in TNF-transgenic mice and restores normal bone mass, suggesting that osteoporosis due to chronic inflammation is a consequence of osteoclast hyperactivity and increased bone resorption, and that TNF promotes generalized bone loss through RANKL  (Fig. 5).
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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