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Rheumatology 2001; 40: 623-630
© 2001 British Society for Rheumatology
Original Papers |
Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint
1 Department of Orthopaedics and Trauma, The University of Adelaide and The Royal Adelaide Hospital, Adelaide 5000, SA, Australia
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Abstract |
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Objective. This study investigated the involvement of the recently identified regulators of osteoclast formation RANKL [receptor activator of nuclear factor kappaB (RANK) ligand, osteoclast differentiation factor, TRANCE, osteoprotegerin ligand] and its natural inhibitor, osteoprotegerin (OPG), in the bone erosion of rheumatoid arthritis (RA).
Methods. mRNA was extracted from cells isolated from the pannus and synovial membrane regions of joints of 11 RA patients. Semiquantitative reverse transcription–polymerase chain reaction was carried out, and the isolated cells were also cultured to determine their ability to form osteoclasts.
Results. mRNAs encoding RANKL, RANK, OPG and macrophage-colony stimulating factor were expressed by cells isolated from RA joints. In addition, mRNA encoding for tumour necrosis factor apoptosis-inducing ligand and the osteoclast markers tartrate-resistant acid phosphatase and calcitonin receptor were also often expressed. Osteoclasts capable of forming resorption lacunae were generated from cells in the RA joints. At 50 ng/ml, recombinant OPG completely inhibited the resorptive activity of these cells. There was a significant correlation between the ratio of RANKL mRNA to OPG mRNA and the number of resorption pits produced (P = 0.028).
Conclusion. These data suggest that RANKL is an essential factor for osteoclast formation by cells in the rheumatic joint and that OPG may prevent the bone erosion seen in RA joints.
KEY WORDS: Bone, Rheumatoid arthritis, Joint damage, Cytokines, Osteoclasts, Osteoprotegerin.
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Introduction |
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Progressive joint destruction is a hallmark of rheumatoid arthritis (RA). The inflammatory changes in RA are associated with the breakdown of both soft tissue and bone in the rheumatoid joint. The bone erosion can be localized to the inflamed joint [1] as well as being generalized, secondary osteoporosis often being associated with RA [2]. Despite the widespread occurrence of RA, we still have an incomplete understanding of the processes of this chronic systemic disease. Most studies have investigated the inflammation that occurs in the soft tissues; however, recent advances in our understanding of bone metabolism allow us now to better investigate the mechanisms of bone loss in RA.
A cell surface molecule, receptor activator of nuclear factor kappaB ligand (RANKL; also called osteoclast differentiation factor, TRANCE and osteoprotegerin ligand) and its receptor, receptor activator of nuclear factor kappaB (RANK) have been shown recently to be key factors stimulating osteoclast formation [3, 4]. It has been shown that the binding of RANKL to RANK on the surface of osteoclast precursors promotes the differentiation of these cells to mature osteoclasts. It is now clear that, together with macrophage-colony stimulating factor (M-CSF), RANKL is required for osteoclast formation. The soluble tumour necrosis factor (TNF) receptor-like molecule osteoprotegerin (OPG) is a natural inhibitor of RANKL [5]. OPG binds to RANKL and prevents its ligation to RANK. The importance of these molecules in regulating bone metabolism is demonstrated by transgenic and gene knockout studies in mice [6]. The relative levels of RANKL and OPG are likely to be important in determining whether osteoclasts will form [7]. As these factors control physiological osteoclast formation, it is reasonable to propose that they may also be key regulators of pathological bone resorption, such as in RA.
It has been reported previously that, under certain conditions, human osteoclasts can be derived from cells present in or near the tissues of arthritic joints [8, 9]. More recently, it has been shown that RANKL is expressed within the rheumatoid joint and that synoviocytes and activated T cells are implicated in its production [10–13]. Moreover, in a mouse model of RA, administration of OPG prevented the bony erosions that often accompany joint inflammation in RA [12]. In the present work, we sought to test the concept that the production of RANKL by cells within the human RA pannus and synovial membrane leads to osteoclastic bone resorption. Cells isolated from the synovial membrane and at the bone–pannus interface were used in this study. We found a positive association between RANKL expression and bone resorption in vitro, and that resorption was completely prevented by exogenous OPG.
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Materials and methods |
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Chemicals
Human recombinant RANKL and OPG were gifts from Amgen (Thousand Oaks, CA, USA).
Patient tissue samples and cell isolation
Tissue samples were taken at surgery from patients who had been diagnosed as suffering from RA, which they had had for 6–25 yr. All patients showed advanced erosion of the bone on X-ray, and had disease that was active but not burnt out, as seen in the late stages of the disease. Details of the samples taken from the patients and of the medication at the time of surgery are shown in Table 1
. The tissue samples were classified as corresponding to either the pannus region adjacent to the bone where erosion was occurring, or to the synovial membrane not adjacent to the bone. In all cases the classification of the tissue was made at the time of surgery by the surgeon (co-author GIB); the pannus tissue was considered to be that part of the synovial membrane that had infiltrated the bone and cartilage. The tissue classified as synovial membrane was capsular synovial tissue separate from bone–cartilage infiltrate. Histology was carried out routinely on samples of these tissues and examples are shown in Fig. 1. Generally, the samples were similar and contained large numbers of infiltrating mononuclear cells. The only major difference was that the pannus tissues did not have a layer of cells lining the surface of the synovial membrane. On removal, the tissue samples were placed immediately into Hanks’ balanced salt solution (HBSS; Gibco BRL, Life Technologies, Melbourne, Australia) then digested at 37°C in calcium- and magnesium-free HBSS solution (Gibco BRL, Life Technologies) containing 1 mg/ml collagenase (Sigma, Castle Hill, Australia) and 1 mg/ml dispase (Sigma). After 60 min, 0.5 mg/ml trypsin in HBSS solution (Sigma) was added, and the tissue was incubated for a further 30 min. Cells were separated from undigested connective tissue with a 70-µm cell sieve (Falcon, Becton Dickinson Labware, Bedford, MA, USA) and the cell suspension was washed once in HBSS. Cells were suspended in RPMI 1640 medium at a concentration of 1x106 cells/ml.
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Cells were isolated from a total of 11 patients with RA, and tissue was taken from two separate sites in two patients. The yield of cells varied depending on the size and the cell density of the tissue sample. An average of 5 x 105 cells from each milligram of wet weight of tissue was obtained. mRNA was extracted from 5 x 105 cells for analysis by reverse transcription–polymerase chain reaction (RT-PCR). Sufficient cells for the studies of osteoclast generation, as described below, were obtained from eight of the patients.
Isolation of human bone-derived cells
Human bone cells were derived as outgrowths from trabecular bone fragments obtained from patients undergoing primary hip replacement, as described previously [14].
Culture of osteoclasts and osteoclast precursors
Cells isolated from the rheumatoid tissues were tested for osteoclast formation and/or activity, as described previously in detail in studies in which the differentiation of monocytes to osteoclasts was promoted by coculture with rodent osteoblastic cells as stromal cells [15]. Briefly, where human bone cells were used as a stromal population, 13-mm diameter sterile glass coverslips or 3.0 x 0.1-mm thick discs of dentine were seeded with human bone-derived cells 24 h before addition of cells isolated from the rheumatoid tissues. Rheumatoid cells [4 x 105 (coverslips) or 2 x 105 (dentine)] were added and after 1 h the non-adherent cells were removed by washing. The individual coverslips and pairs of dentine slices were placed in 16-mm diameter wells with 1 ml of 
MEM medium containing 10 - 8 M 1,25(OH)2D3 (vitamin D3), 10 - 8 M dexamethasone (Fauldings, Adelaide, Australia) and 25 ng/ml recombinant human M-CSF (a kind gift from the Genetics Institute, Cambridge, MA, USA). Medium was replenished every 3 days throughout the experiment and all experiments were carried out in duplicate for each rheumatoid sample.
Tartrate-resistant acid phosphatase (TRAP)
After 1 or 14 days of culture, cells staining positive for TRAP were quantitated using a commercial staining kit (Sigma).
Identification of resorption pit formation
To assess the extent of bone resorption by cells in the cocultures, dentine discs were examined for resorption lacunae on day 14, as described previously [14].
Preparation of total RNA and RT-PCR analysis
The total cell population isolated from pannus or synovial membrane, as described above, was lysed by the addition of Trizol reagent (Life Technologies, Gaithersburg, MD, USA) and total RNA was prepared according to the manufacturer's instructions. cDNA was synthesized using an AMV RT cDNA kit (Promega, Madison, WI, USA). cDNA was amplified by PCR in a thermal cycler (Eppendorf, Hamburg, Germany). Each amplification mixture contained 1 µl of the cDNA sample or water control, 0.2 mM dNTPs and 1 U of Platinum Taq DNA polymerase (Life Technologies), 100 ng each of 5' and 3' primers, 1.5 mM MgCl2, 2 µl 10x reaction buffer, and sterile diethyl pyrocarbonate H2O. Twenty-two cycles of PCR were performed for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and 30–34 cycles for the other primer pairs. Primer sequences and predicted PCR product sizes have been published previously [15, 16]. Amplification products were resolved by electrophoresis on a 2% w/v agarose gel and post-stained with SYBR Gold (catalogue no. S-11494; Molecular Probes, Eugene, OR, USA). The intensity of the PCR products was quantified using a Molecular Imager Fx fluorescent scanner and Quant-1 software (Bio-Rad, Hercules, CA, USA). Preliminary experiments were performed to ensure that the number of PCR cycles was within the exponential phase of the amplification curve. This allowed semiquantitative comparisons to be made between the levels of expression of the various RNA species in the samples, as described previously [15, 16].
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Results |
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Expression of regulators of osteoclast formation in rheumatoid tissues (RT-PCR)
Figure 2
shows PCR products corresponding to mRNA for RANKL, OPG and M-CSF, as determined by RT-PCR, in cells digested from rheumatoid tissues sampled from 11 patients. PCR products corresponding to each of the mRNA species could be amplified from nearly all tissue samples. We also observed that TRAIL, a TNF--related molecule that has been shown to bind to and antagonize the inhibitory actions of OPG [17, 18], was expressed in all the samples tested. mRNA encoding for the osteoclast markers TRAP and calcitonin receptor (CTR) were also expressed in many of the rheumatoid tissues. TRAP was expressed in all but two samples. In contrast, CTR was expressed in all the pannus tissue samples but only one of the synovial membrane samples.
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Generation of osteoclasts from rheumatoid tissues
The population of cells digested from RA tissues that were adherent to glass coverslips contained many cells with the appearance of osteoclasts after culture for 24 h (Fig. 3a). These osteoclast-like cells were large and TRAP-positive and contained many nuclei. This suggested that osteoclast-like cells were resident in the arthritic tissues. Many more osteoclastic cells were seen after 14 days of culture, at which time large multinucleated TRAP-staining cells were seen regularly amongst cells cultured either alone (Fig. 3b) or in the presence of human osteoblast-like cells. Addition of exogenous OPG did not markedly affect the number of TRAP-positive cells that formed from RA cells alone (Fig. 3c) or RA cells cultured with human bone-derived cells. When RA cells were cultured alone on dentine slices, large numbers of resorption lacunae were usually seen by day 14 (Fig. 3d). Slightly more resorption pits were observed when RA cells were cultured with human bone-derived cells (Fig. 3e). Treatment with 50 ng/ml OPG completely inhibited the formation of resorption pits in cultures of RA cells alone (Fig. 3f) and in cocultures of RA cells with human bone-derived cells. Using inverted-phase microscopy, resorption pits could be observed during the culture period, and no pits were seen before day 7. The numbers of resorption pits and TRAP-positive cells seen at day 14 are compared in Table 2. Culturing the RA cells in the presence of human bone-derived cells resulted in a slight increase in the mean numbers of resorption pits and cells expressing TRAP compared with cells incubated alone. Although OPG treatment resulted in complete inhibition of pit formation, there was no reduction in the number of cells expressing TRAP, as stated above.
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There is growing experimental evidence [7] that (i) RANKL and OPG mRNA levels are good surrogates for the expression of the corresponding proteins, and (ii) that osteoclastic resorption is dependent upon the effective concentration of RANKL, which is in turn determined by the local concentration of OPG. We therefore compared the ratio of RANKL mRNA to OPG mRNA, as measured by RT-PCR, with the numbers of resorption pits produced by cells digested from the RA tissues cultured alone (Fig. 4
). There was a strong positive correlation between these values [Spearman rank (non-parametric) correlation 0.762; P = 0.028], consistent with a role for RANKL in promoting osteoclastic bone resorption in human RA tissues. A similar comparison of the numbers of resorption pits with the ratio of TRAIL mRNA to OPG mRNA was carried out but no significant correlation was noted (P > 0.05), indicating that TRAIL may have less of a role than OPG and RANKL in regulating osteoclast formation in this pathology.
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Inhibition of osteoclast formation by OPG
Cells isolated from RA tissues were cultured on dentine slices in the presence of 50 ng/ml OPG to determine whether RANKL expressed by the cells was essential for the formation of osteoclasts. As shown pictorially in Fig. 3
, OPG completely inhibited the ability of rheumatoid cells to form resorption lacunae (Table 2). This inhibition occurred in the presence or absence of added human bone cells. Interestingly, the numbers of cells expressing TRAP was only slightly reduced by OPG treatment.
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Discussion |
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This study has shown that bone-resorbing osteoclasts can be generated in culture from cells present within the RA joint. The data indicate that these tissues contain both mature osteoclasts and their precursors, as well as producing factor(s) essential for osteoclast formation. Our results show that RANKL mRNA is expressed in cells within the RA tissues, and the ratio of RANKL mRNA to the mRNA of its inhibitor, OPG, expressed in the RA tissues significantly correlated with the formation of functional osteoclasts. These results are supported by recent reports showing the expression of RANKL and RANK in rheumatoid tissues in humans [11, 13] and in animal models [12, 19].
Our results differ from a previous report [8] which found that additional rat osteoblast-like cells were required for RA synovial macrophage and blood monocytes to produce osteoclastic resorption. The reason for the difference may be that we mainly used cells isolated from tissue adjacent to bone, corresponding to the invading pannus, whereas the previous study used synovial macrophages and blood monocytes from the RA patients. More studies would need to be carried out to determine if indeed there are functional differences in osteoclast formation in these different regions of synovial tissues. It is significant to note the relationship between the ratio of RANKL mRNA to OPG mRNA and osteoclast formation. These data suggest a correlation between the mRNA levels of RANKL and OPG and the corresponding protein levels. In addition, our findings support the concept that the relative levels of RANKL and OPG is a key factor in determining bone loss in these tissues.
Although we found abundant expression of M-CSF mRNA in cells digested from RA tissues, it is clear that M-CSF, an essential cofactor for the induction of osteoclast differentiation by RANKL, is limiting in human osteoclastogenesis in culture [4]. As in other studies [8, 13], M-CSF was included in all our cell cultures as it allowed us to investigate the activities of RANKL independently of a requirement for M-CSF.
The number of multinucleated TRAP-positive cells that developed from cells isolated from the rheumatoid tissues was not markedly reduced by OPG treatment, while OPG treatment totally prevented resorption pit formation, as reported previously [13]. This may indicate that osteoclast precursors in the rheumatoid tissues have differentiated further towards becoming mature osteoclasts than the less differentiated cells in the peripheral monocyte population, as TRAP expression is markedly inhibited by OPG in culture systems using peripheral blood monocytes [3, 4]. While development of the rheumatoid cells into multinucleated TRAP-positive cells may not be affected by inhibiting RANKL with OPG, RANKL does appear to be required to stimulate and maintain osteoclastic bone resorption in these tissues. This concept is further supported by the observation that TRAP mRNA was expressed by cells isolated from most of the patient tissue samples, but strong expression did not always correlate with the formation of resorption pits by cells isolated from these tissues.
CTR expression may be a more appropriate indicator of osteoclast differentiation than TRAP expression in this pathology. CTR was expressed in all the pannus samples but in only one of the synovial membrane samples. This is consistent with a recent report, using in situ hybridization, showing that CTR mRNA is not expressed in the synovial membrane but is expressed in the tissue–bone interface in RA [11]. CTR was also consistently expressed in rheumatoid tissues from which osteoclasts readily formed, further supporting the concept that CTR expression is associated with the later stages of osteoclast differentiation.
RANKL has been shown to be required for osteoclast formation, and is normally provided by osteoblast-like cells in bone [3, 4]. Recent reports indicate that stromal support may be provided by either synovial fibroblasts [11, 13] or lymphocytes present in the rheumatoid tissues [10, 12]. Horwood et al. [10] showed that CD3 + T cells from the human rheumatoid joint express RANKL and can promote osteoclast formation from rodent spleen cell precursors. Kong et al. [12] demonstrated that, in addition to the production of RANKL by lymphocytes, the inhibition of RANKL by OPG treatment in vivo reduced both bone and cartilage destruction in a model of adjuvant arthritis in rats. Our study strongly supports these findings and suggests that OPG may be similarly efficacious in human RA.
Other mediators known to be produced by inflammatory cells in the soft tissues of the RA joint may promote bone loss indirectly by inducing the expression of RANKL. The inflammatory mediators interleukin (IL) -1ß and TNF- have been shown to stimulate RANKL mRNA expression [20], and prostaglandin E2 is reported to enhance the stimulation of osteoclast formation by RANKL [21]. IL-17 is also present in synovial fluids in RA and has similarly been reported to stimulate osteoclastogenesis [22]. In addition, inflammatory chemokines produced in the inflamed joint may also contribute to osteoclast formation directly [23] or by attracting monocyte osteoclast precursors [8].
It might be significant that TRAIL mRNA was consistently expressed by cells isolated from RA tissues. TRAIL is a TNF--related molecule that induces apoptosis; however, it has also been shown to bind OPG and is able to suppress the inhibitory action of OPG in osteoclast formation [17, 18]. Its expression in the RA joint may therefore represent an additional pro-osteoclastogenic influence. A recent report has demonstrated that TRAIL may suppress lymphocyte proliferation and have anti-inflammatory activity in an animal model of arthritis [24]. This is the first report of the presence of TRAIL expression in tissues of the human RA joint. Further studies will be needed in humans to determine whether TRAIL produced in the RA joint is involved in regulating both bone loss and inflammation in this pathology.
It is possible that bone lysis and the cytokines that cause it also contribute to the progression of inflammation in RA. In the rodent model of adjuvant arthritis, treatment with OPG reduced both cartilage and bone destruction but did not reduce inflammation [12]. This has yet to be demonstrated for human RA. However, in the light of our results here, the separate consideration of inflammation and bone treatment may result in specific targeted treatments for these two components of human RA.
Bone loss is a major cause of the loss of function of the human RA joint. Therefore, inhibiting this bone loss would be of great assistance to patients with RA. Alone, or in combination with anti-inflammatory therapies, treatments that inhibit osteoclast formation may help maintain joint function. There is now good evidence that OPG is effective in treating the bone loss seen in an animal model of this disease [12]. Together with the results presented here, this raises the exciting possibility that OPG, or a structural mimetic of OPG, might be useful in maintaining joint function for sufferers of RA.
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Acknowledgments |
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The authors thank Mr Dale Caville for photographic assistance and Professor Barrie Vernon-Roberts for helpful advice. This work was supported by the National Health and Medical Research Council of Australia and the University of Adelaide Faculty of Medicine.
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Notes |
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Correspondence to: D. R. Haynes.
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