Murine models of human disease have contributed significantly to our understanding of the pathophysiology of disease and played
a key role in development of new treatments. The study of myeloma bone disease is no exception. In recent decades we have
seen the development of a number of different models of myeloma bone disease. These include the syngeneic models, such as
the 5TMM series, and the SCID models, including the SCID-hu model and those based upon engraftment of human cell lines. They
have contributed directly to the identification of key molecules such as MIP-1α, facilitated establishing a critical role
for the RANKL pathway, and been used to identify new agents for treatment including RANKL inhibition therapies and the bisphosphonates.
More recently, they have been used to establish the role for osteoblast inhibition in the development of myeloma bone disease
and contributed to the study of molecular pathways that regulate osteoblast suppression. In addition, these models have played
a key role in understanding the importance of the bone microenvironment in supporting myeloma cell growth and survival in
bone. It is likely that further refinements to our understanding of these models will lead to further insights into the mechanisms
of myeloma bone disease. Murine models of myeloma bone disease will remain central to the development of new therapeutic approaches
to treating this important clinical feature of myeloma.
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma is a B-cell malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells express the receptor activator of nuclear factor kappaB ligand (RANKL), induce RANKL expression in the bone marrow, and down-regulate expression of the decoy receptor osteoprotegerin, thereby promoting bone resorption. Targeting this system in myeloma has clear therapeutic potential. However, osteoprotegerin also binds tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and prevents TRAIL-induced apoptosis of myeloma cells. Whether or not osteoprotegerin can bind TRAIL and prevent apoptosis in vivo and the relative importance of osteoprotegerin binding to TRAIL and RANKL are unclear. In the present study, we have investigated the ability of an osteoprotegerin-like peptidomimetic (OP3-4), designed to block the RANKL/RANK interaction, to inhibit osteoclastic bone resorption and TRAIL-induced apoptosis in vitro and myeloma bone disease in vivo. OP3-4 inhibited osteoclast formation (P < 0.01) and bone resorption (P < 0.01) in vitro. However, OP3-4 had no effect on TRAIL-induced apoptosis of RPMI 8226 myeloma cells. Treatment of 5T2MM myeloma-bearing mice with OP3-4 decreased osteoclast number and the proportion of bone surface covered by osteoclasts (P < 0.05). Treatment also prevented the tumor-induced decrease in cancellous bone area and the development of osteolytic lesions (P < 0.05). OP3-4 also reduced tumor burden when compared with the control (P < 0.05). These data suggest that OP3-4 and the selective inhibition of RANKL, but not TRAIL activity, are effective in preventing myeloma bone disease and offer a novel therapeutic approach to treating this aspect of myeloma. [Cancer Res 2007;67(1):202-8].
Cancer Research 02/2007; 67(1):202-8. DOI:10.1158/0008-5472.CAN-06-1287 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myeloma tumour growth, except in the most advanced stages of the disease, is restricted to the bone marrow. We used the severe combined immunodeficient-human (SCID-hu) host system, in which primary human myeloma cells grow in, disseminate to and interact with a human microenvironment, to study the interactions between myeloma cells and cells in the bone marrow microenvironment. We used inhibitors of osteoclast activity to determine the role of osteoclasts and their products in supporting myeloma cell growth. Treatment of myelomatous SCID-hu hosts with an inhibitor of osteoclast activity (pamidronate or zoledronate) or with a specific inhibitor of the receptor activator of NF-kappaB ligand (RANKL) halted myeloma-induced bone resorption, when present, and resulted in inhibition of myeloma cell growth and survival. In contrast, myeloma cells from patients with extramedullary disease had a different growth pattern in the SCID-hu hosts and were not inhibited by these interventions, indicating that, while still dependent on a human microenvironment, these cells no longer required the bone marrow microenvironment for survival. This study demonstrates the dependence of myeloma cells on osteoclast activity and their products, and highlights the importance of the myeloma-osteoclast-myeloma loop for sustaining the disease process. Breaking this loop may help control myeloma.
British Journal of Haematology 03/2002; 116(2):278-90. DOI:10.1046/j.1365-2141.2002.03257.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myeloma causes a devastating and unique form of osteolytic bone disease. Although osteoclast activation is responsible for bone destruction, the precise mechanisms by which myeloma cells increase osteoclast activity have not been defined. An animal model of human myeloma bone disease would help in clarification of these mechanisms. Multiple myeloma occurs spontaneously in aging C57 BL/KaLwRij mice and has all of the features of the disease in humans, including the characteristic bone lesions. The disease can be induced in normal C57 BL/KaLwRij mice by inoculation of fresh marrow-derived cells from mice with myeloma, but this model is difficult to study because of variability in the number of myeloma cells in marrow-derived preparations. To develop a better animal model of human myeloma bone disease, we have established and subcloned a cell line from this murine myeloma and found that it causes osteolytic bone lesions in mice characteristic of human myeloma bone disease. The cell line produces interleukin-6, but grows independent of exogenous interleukin-6. Mice inoculated intravenously with the cultured cells predictably develop an identical disease to the mice injected intravenously with fresh bone-marrow-derived myeloma cells, including monoclonal gammopathy and radiologic bone lesions. We found that some of the mice became hypercalcemic, and the bone lesions are characterized by increased osteoclast activity. We found identical results when we inoculated Nu/Bg/XID mice with cultured murine myeloma cells. Because we can inoculate mice with precise numbers of cells and predict accurately when the mice will develop bone lesions, become hypercalcemic, and die, this should be a convenient model for determining the mechanisms by which the myeloma cells cause osteoclast activation in this model of human myeloma bone disease.
Bone 07/1997; 20(6):515-20. DOI:10.1016/S8756-3282(97)00056-2 · 3.97 Impact Factor
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