Abstracts of 2nd Scientific Meeting on Bone Disease in Multiple Myeloma

The RANK ligand / osteoprotegerin system and myeloma bone disease

Peter Croucher: Division of Genomic Medicine, Unversity of Sheffield Medical School, Sheffield UK

Multiple myeloma is characterised by the proliferation of myeloma cells in the bone marrow and is often associated with the development of osteolytic bone lesions, pathological fractures and hypercalcaemia. However, the factors that mediate the development of myeloma bone disease are unclear. Recently, the receptor activator of NF-kB ligand (RANKL) system has been shown to play an important role in normal osteoclast development. RANKL, which is expressed by bone marrow stromal cells, associates with the signalling receptor RANK, expressed by osteoclast precursors, and promotes osteoclast differentiation. In addition, a soluble decoy receptor, osteoprotegerin (OPG), has also been identified which binds to RANKL, prevents its association with RANK and inhibits osteoclast formation. Since myeloma cells promote the development of osteolytic bone lesions by increasing osteoclast formation, it is likely that myeloma cells may be able to alter the local regulation of the RANKL system in favour of an increase in bone resorption. This could be achieved in a number of ways. Myeloma cells may be able to promote an increase in expression of RANKL by cells in the local bone marrow microenvironment, which in turn could stimultate osteoclast formation. Myeloma cells themselves may express RANKL and interact directly with osteoclast precursors to promote osteoclast formation. Alternatively, the presence of myeloma cells in the local bone marrow microenvironment may result in a decrease in the local production of OPG, removing an inhibitor of osteoclast formation.

Recent studies have demonstrated that interactions between murine myeloma cells and stromal cells results in an increase in RANKL expression in stromal cells and myeloma cells (Oyajobi et al., 1998). In addition, using RT-PCR we have shown that a range of human myeloma cell lines express the mRNA for RANKL. Furthermore, flow cytometric studies have demonstrated that permeabilised myeloma cells also express RANKL. However, expression can not be detected on live cells suggesting that RANKL is not expressed on the surface of myeloma cell lines (Shipman et al., 2000). These data contrast with that seen in primary myeloma cells isolated from the bone marrow of patients with myeloma. Flow cytometric studies demonstrate that RANKL is expressed on the surface of syndecan-1 positive myeloma cells in each of the patient samples examined. These data suggest that primary myeloma cells, but not myeloma cell lines express RANKL, on the cell surface, which would give them the capacity to induce osteoclast formation directly (Shipman et al., 2000). Furthermore, recent data have also suggested that myeloma cells can decrease OPG production by stromal cells (Sordillo et al., 2000). These data suggest that myeloma cells may be able to modulate RANKL and OPG expression in the local bone marrow microenvironment in favour of promoting bone resorption.

Since myeloma cells have the ability to promote osteoclast formation, targeting the RANKL system may prevent the development of myeloma bone disease. We have investigated this in the 5T2MM murine model of multiple myeloma. In this model 5T2MM cells 'home' to the bone marrow which results in the development of osteolytic bone disease. This is characterised by the presence of osteolytic bone lesions, a decrease in total bone mineral density, a reduction in cancellous bone volume, and an increase in the numbers of tartrate-resistant acid phosphatase positive osteoclasts . C57BL/KaLwRij mice were injected with 5T2MM myeloma cells and the development of myeloma monitored by measuring serum paraprotein. After eight weeks all animals injected with tumour cells develop the myeloma disease. Treatment of animals, with established myeloma, with a recombinant OPG fusion protein (FcOPG) results in a decrease in the number of osteolytic lesions (Croucher et al., 2000). Treatment is associated with a partial preservation of the decrease in cancellous bone volume induced by the tumour cells and an inhibition of osteoclast formation. In addition treatment was also associated with an increase in total bone mineral density. Treatment of mice, with established myeloma, with FcOPG had no effect on serum paraprotein or the proportion of myeloma cells in the bone marrow (Croucher et al., 2000). These data are supported by the demonstration that a soluble RANK fusion protein is also effective at inhibiting the development of myeloma bone disease in 5TGM1 murine model and the Scid/Hu model of myeloma (Oyajobi et al., 2000 and Pearse et al., 2000). Interestingly, the two latter studies have suggested that inhibiting the RANKL system may also result in an anti-tumour effect.

Taken together these data suggest that myeloma cells may not only have the ability to promote RANKL expression in the bone marrow microenvironment but also express RANKL themselves. Modulating the RANKL system in this way is likely to contribute to the increase in osteoclast formation and bone resorption seen in this disease. Targeting the RANKL system with FcOPG or other antagonists appears to be effective in preventing the development of myeloma bone disease. It remains possible that such antagonists may represent novel thereapeutic approaches to managing this important clinical feature of multiple myeloma.

References

Croucher, P.I., Shipman, C.M., Perry, M.J., Lippitt, J.M. Asosingh, K., van Beek, E.J.R., Van Camp, B., Russell, R.G.G., Dunstan, C., Vanderkerken, K. (2000) Osteoprotegerin (OPG) inhibits the development of osteolytic bone disease in the 5T2MM model of multiple myeloma. ASH 2000.

Oyajobi, B.O., Traianedes, K., Yoneda, T., Mundy, G.R. (1998) Expression of Rank ligand (RankL) by myeloma cells requires binding to bone marrow stromal cells via an a4b1-VCAM-1 interaction. Bone 23:S181. [medline abstract not available]

Oyajobi, B.O., Garrett, I.R., Williams, P.J., Yoneda, T., Anderson, D.M., Mundy, G.R. (2000) A soluble murine receptor activator of NF-kB-human immunoglobulin fusion protein (RANK.Fc) inhibits bone resorption in a murine model of human multiple myeloma bone disease. J. Bone Miner. Res. 15Suppl1:S176. [medline abstract not available]

Pearse, R.N., Sordillo, E.M., Yoccoby, S., Wong, B.R., Liau, D.F., Coleman, N., Michaeli, J., Epstein, J., Choi, Y. (2000) Administration of the TRANCE-antagonist TR-Fc limits myeloma-induced bone destruction. ASH 2000.

Shipman, C.M., Holen, I., Lippitt, J.M., Vandenberghe, E., Croucher, P.I. (2000) Tumour cells isolated from patients with multiple myeloma express the critical osteoclastogenic factor, RANKL. ASH 2000.

Sordillo, E.M., Wong, B.R., Liau, D.F., Coleman, N., Michaeli, J., Choi, Y., Pearse, R.N. (2000) Multiple myeloma disrupts the TRANCE/OPG cytokine axis. ASH 2000

 

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