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© 2002 American Society for Clinical Oncology
Human Bone Marrow Myeloma Cells Express RANKLUniversitätsklinikum Charité, Berlin, Germany To the Editor:A stimulating review by Roodman on the biology of osteoclast activation in cancer was published in the August 1, 2001, issue of the Journal of Clinical Oncology,1 which we read with great interest. Increased bone resorption is a hallmark of multiple myeloma. In myeloma, bone is destroyed by osteoclasts which accumulate only on bone-resorbing surfaces adjacent to myeloma cells and are not increased in bone not invaded by myeloma cells. In his review, Roodman pointed out (1) that receptor activator of NF-kappaB ligand (RANKL) is a potent osteoclastogenic factor that activates its specific receptor, receptor activator of NF-kappaB (RANK), which is located on osteoclasts, and (2) that RANKL is likely to be an important factor mediating bone destruction in myeloma patients. He suggested that RANKL is not produced by myeloma cells but by marrow stromal cells in response to myeloma. Human multiple myeloma cell lines have been shown to express RANKL.2,3 Therefore, we analyzed the expression of RANKL protein on bone marrow plasma cells from patients with multiple myeloma. Flow cytometry was performed using bone marrow aspirates from 10 patients with multiple myeloma and osteolytic lesions. Plasma cells were identified as CD38 strongly positive (++) and CD138 (B-B4)-positive (+) cells, as described previously.4 Immunofluorescence staining of RANKL on the cell surface was performed using a monoclonal mouse antibody against human RANKL (R&D Systems Inc, Minneapolis, MN) and its isotype control (mouse immunoglobulin G2b), labeled with phycoerythrin. The mean fluorescence index for RANKL and the percentage of RANKL-positive plasma cells were determined. We could detect a strong expression of RANKL on bone marrow plasma cells in all multiple myeloma patients investigated (Fig 1). The median mean fluorescence index of bone marrow plasma cells was 134 (range, 32 to 350), and the median percentage of plasma cells expressing RANKL was 91% (range, 73% to 98%). These findings show that RANKL is directly expressed by plasma cells in the bone marrow of myeloma patients with osteolytic bone lesions and suggest a direct role of this ligand in the osteoclast activation in multiple myeloma.
Osteoprotegerin (OPG) acts as a decoy receptor for RANKL and neutralizes its biologic effects.5 Our findings are of clinical interest since systemic application of OPG reduces bone resorption in post-menopausal women6 and may be used to correct the imbalance of the RANKL-OPG axis in multiple myeloma. REFERENCES
1.
Roodman GD: Biology of osteoclast activation in cancer. J Clin Oncol 19: 3562-3571, 2001 2. Westin JS, Ljunghall S, Nilsson K, et al: Human multiple myeloma cell lines express mRNA for osteoclast differentiation factor. J Bone Miner Res 14: S225, 1999 (suppl 1, abstr) 3. Altamirano CV, Ma HJ, Parker KM, et al: RANKL is expressed in malignant multiple myeloma cell lines. Blood 96: 365a, 2000 (suppl 1, abstr)
4.
Sezer O, Heider U, Zavrski I, et al: Differentiation of monoclonal gammopathy of undetermined significance and multiple myeloma using flow cytometric characteristics of plasma cells. Haematologica 86: 837-843, 2001 5. Hofbauer LC, Neubauer A, Heufelder AE: Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin. Cancer 92: 460-470, 2001[CrossRef][Medline] 6. Bekker PJ, Holloway D, Nakanishi A, et al: The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 16: 348-360, 2001[CrossRef][Medline]
ResponseUniversity of Texas Science Center at San Antonio, San Antonio, TX In Reply:Thank you for your letter. Several groups, including the data you have provided, have found that myeloma cells themselves express receptor activator of NF-kappaB ligand (RANKL), although the levels of RANKL expression have been variable. In contrast to the results that you report, others, such as Pearse et al,1 have not detected RANKL expression by myeloma cells in bone marrow biopsy specimens from patients with myeloma. These researchers found that RANKL was not expressed by myeloma cells in the 14 bone marrow biopsy specimens from myeloma patients they examined either by immunocytochemistry, in situ hybridization, or polymerase chain reaction. They found that RANKL expression was increased in multiple myeloma–infiltrated marrow but that RANKL was expressed by activated T cells and stromal cells and not by myeloma cells. Furthermore, they could not find RANKL expression by myeloma cell lines ARP-1, U266, RPM18226, H929, and ARH-77, as assessed by receptor activator of NF-kappaB (RANK)-Fc binding or by reverse transcriptase polymerase chain reaction. Although expression of RANKL by myeloma cells is shown very nicely by your results and those of others, it has not been a consistent finding by all investigators. The most consistent finding by most investigators is that RANKL expression is increased in marrow stromal cells from myeloma patients. REFERENCES
1.
Pearse RN, Sordillo EM, Yaccoby S, et al: Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci U S A 98: 11581-11586, 2001
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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