- Email: [email protected]
Have myeloma cells osteoclast-like activity?
Available online at www.sciencedirect.com
Leukemia Research 32 (2008) 521–522
Editorial
Have myeloma cells osteoclast-like activity? Implications into the pathogenesis of myeloma bone disease Bone disease is one of the most debilitating manifestations of multiple myeloma characterized by the development of osteolytic lesions, pathological fractures and hypercalcemia. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. The pathophysiology of myeloma bone disease has been studied extensively over recent years. Myeloma cells promote osteoclastic bone resorption and suppress osteoblast activity, thereby causing an imbalance between the processes of bone resorption and formation, leading to bone loss [1]. Several molecules that are produced in the bone marrow microenvironment by myeloma or stromal cells are responsible for the activation of osteoclasts, such as the receptor activator of nuclear factor-kappa B ligand, macrophage inflammatory protein-1 alpha, macrophage colony stimulating factor, interleukin 6 (IL-6), IL-1beta, IL-11, etc. Furthermore, the production of Wingless-type signaling inhibitors by myeloma cells, such as dickkopf-1 and frizzled-related proteins, disrupts osteoblast function, thus enhancing the development of bone lytic disease [1–3]. Based on these, it is widely accepted that bone destruction in MM is caused by osteoclasts that are considered to be the only cells able to degrade bone and not by the myeloma cells themselves. However, recent in vitro data have shown that myeloma cells can also act as osteoclasts. By extending standard cultures of U-266 and MCC-2 myeloma cell lines, Calvani et al. observed that subsets of adherent cells expressed osteoclast phenotype, including multinuclear morphology, cytoplasmic tartrate-resistant acid phosphatase, calcitonin receptor (CTR) and specific osteoclast antigens. These subsets resorbed bone substrates by producing osteoclast enzymes as well as the characteristic redistribution of F-actin in their cytoskeleton, thus forming the sealing zone that is adopted by adherent osteoclasts to generate the acidified environment essential for bone resorption [4]. These results are in accordance with those of McDonald et al. who showed several years ago that myeloma cells of a mouse plasmacytoma model were able to independently destroy bone [5]. Moreover, FISH and immunohistochemistry analyses 0145-2126/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2007.08.018
on bone sections demonstrated that bone-resorbing osteoclasts from myeloma patients contain nuclei with translocated chromosomes of myeloma clone origin at a proportion of 30% of the total osteoclast population [6]. Interestingly, the occurrence of these osteoclast–myeloma clone hybrids correlated with the proximity of myeloma cells, while similar hybrid cells were generated in myeloma cell–osteoclast cocultures indicating that hybrid cells can originate through fusion between myeloma cells and osteoclasts [6]. These data suggest that we may have underestimated the direct role of myeloma cells in bone resorption. In an attempt to better clarify this role, Silvestris et al. published in this issue of Leukemia Research that malignant plasma cells from U-266, RPMI 8226 and MCC-2 myeloma cell lines are able to exert an erosing activity on both calcium phosphate and dentin discs in vitro, resembling the inorganic and organic bone, respectively [7]. Furthermore, both primary myeloma cells and plasma cell lines express CTR-2, the widespread isoform of CTR, at higher intensity compared to plasma cells of monoclonal gammopathy of undetermined significance and control cell lines. CTR activation by CT was able to enhance both cAMP and Ca++ flow and subsequently activate protein kinase A and protein kinase C pathways in malignant plasma cells as in normal osteoclasts, leading to inhibition of their bone resorption function. The inhibition of the formation of erosive lacunae made by malignant plasma cells in the presence of CT supports an osteoclast functional differentiation of malignant plasma cells in vitro [7]. These in vitro results suggest that the activation of CTR by CT could inhibit bone resorption produced by both osteoclasts and myeloma cells. However, this has not been translated to a beneficial effect of CT in the management of bone disease of myeloma patients. Although CT produced an increase in trabecular bone volume, cortical thickness, osteoid volume and osteoid seam thickness index and reduced the osteoclast resorption surface in 11 MM patients [8], it did not reduce skeletal related events in other studies [9], possibly due to the down regulation of CTR expression. Current management of myeloma bone disease includes the use of bisphosphonates that are potent osteoclast
522
Editorial / Leukemia Research 32 (2008) 521–522
inhibitors. Novel anti-myeloma agents, such as proteasome inhibitors and immunomodulatory drugs seem to reduce bone resorption and possibly increase bone formation in these patients [10]. The knowledge that a subset of myeloma cells may also have osteoclast-like activity is important as it may reveal novel pathways for the development of new anti-myeloma agents. Furthermore, it will help us to better understand the biology of myeloma bone disease as we know that there are patients who show a tumor reduction due to anti-myeloma therapy, i.e. they achieve a reduction in paraprotein levels and plasma cell infiltration of the bone marrow, but they continue to develop new lytic lesions. A subset of myeloma cells with osteoclast-like activity that is resistant to the administered therapy may be probably responsible for such a phenomenon. Furthermore, the possibility that malignant plasma cells corrupt host cells by the transfer of malignant DNA, producing hybrid cells may have been undervalued in myeloma research to-date. However, the osteoclast-like activity of all or a subset of myeloma cells has to be confirmed in myeloma patients. The paper of Silvestris et al. drives researchers of myeloma bone disease to investigate this field also. Acknowledgements There is nothing to acknowledge for this Editorial. References [1] Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management. Ann Oncol 2005;16:1223–31. [2] Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J, et al. Soluble receptor activator of nuclear factor kappaB ligandosteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003;102:1064–9. [3] Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy Jr JD. Antibody-based inhibition of DKK1 suppresses tumor-induced
[4]
[5]
[6]
[7]
[8]
[9]
[10]
bone resorption and multiple myeloma growth in vivo. Blood 2007;109:2106–11. Calvani N, Cafforio P, Silvestris F, Dammacco F. Functional osteoclastlike transformation of cultured human myeloma cell lines. Br J Haematol 2005;130:926–38. McDonald DF, Schofield BH, Prezioso EM, Adams VL, Frondoza CA, Trivedi SM, et al. Direct bone resorbing activity of murine myeloma cells. Cancer Lett 1983;19:119–24. Andersen TL, Boissy P, Sondergaard TE, Kupisiewicz K, Plesner T, Rasmussen T, et al. Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer-host partnership? J Pathol 2007;211:10–7. Silvestris F, Cafforio P, De Matteo M, Quatraro C, Dammacco F. Expression and function of the calcitonin receptor by myeloma cells in their osteoclast-like activity in vitro. Leukemia Res 2008;32: 611–23. Rico H, Hernandez ER, Diaz-Mediavilla J, Alvarez A, Martinez R, Espinos D. Treatment of multiple myeloma with nasal spray calcitonin: a histomorphometric and biochemical study. Bone Miner 1990;8:231–7. Bataille R, Tenoudji-Cohen M, Rossi JF. Multiple myeloma: optimal use of salmon calcitonin in the management of myeloma osteoclastic bone disease. Br J Haematol 1983;53:170–1. Terpos E, Dimopoulos MA, Sezer O. The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma. Leukemia 2007;21:1875–84.
Evangelos Terpos a,b,∗ Department of Hematology and Medical Research, 251 General Air Force Hospital, Athens, Greece b Department of Hematology, Faculty of Medicine Imperial College London, London, UK a
∗ Correspondence
address: Department of Hematology and Medical Research, 251 General Air Force Hospital, 3 Kanellopoulou Street, GR-11525, Athens, Greece. Tel.: +30 210 7463803; fax: +30 210 7464676. E-mail addresses: [email protected], [email protected] 23 August 2007 Available online 3 October 2007
Leukemia Research 32 (2008) 521–522
Editorial
Have myeloma cells osteoclast-like activity? Implications into the pathogenesis of myeloma bone disease Bone disease is one of the most debilitating manifestations of multiple myeloma characterized by the development of osteolytic lesions, pathological fractures and hypercalcemia. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. The pathophysiology of myeloma bone disease has been studied extensively over recent years. Myeloma cells promote osteoclastic bone resorption and suppress osteoblast activity, thereby causing an imbalance between the processes of bone resorption and formation, leading to bone loss [1]. Several molecules that are produced in the bone marrow microenvironment by myeloma or stromal cells are responsible for the activation of osteoclasts, such as the receptor activator of nuclear factor-kappa B ligand, macrophage inflammatory protein-1 alpha, macrophage colony stimulating factor, interleukin 6 (IL-6), IL-1beta, IL-11, etc. Furthermore, the production of Wingless-type signaling inhibitors by myeloma cells, such as dickkopf-1 and frizzled-related proteins, disrupts osteoblast function, thus enhancing the development of bone lytic disease [1–3]. Based on these, it is widely accepted that bone destruction in MM is caused by osteoclasts that are considered to be the only cells able to degrade bone and not by the myeloma cells themselves. However, recent in vitro data have shown that myeloma cells can also act as osteoclasts. By extending standard cultures of U-266 and MCC-2 myeloma cell lines, Calvani et al. observed that subsets of adherent cells expressed osteoclast phenotype, including multinuclear morphology, cytoplasmic tartrate-resistant acid phosphatase, calcitonin receptor (CTR) and specific osteoclast antigens. These subsets resorbed bone substrates by producing osteoclast enzymes as well as the characteristic redistribution of F-actin in their cytoskeleton, thus forming the sealing zone that is adopted by adherent osteoclasts to generate the acidified environment essential for bone resorption [4]. These results are in accordance with those of McDonald et al. who showed several years ago that myeloma cells of a mouse plasmacytoma model were able to independently destroy bone [5]. Moreover, FISH and immunohistochemistry analyses 0145-2126/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2007.08.018
on bone sections demonstrated that bone-resorbing osteoclasts from myeloma patients contain nuclei with translocated chromosomes of myeloma clone origin at a proportion of 30% of the total osteoclast population [6]. Interestingly, the occurrence of these osteoclast–myeloma clone hybrids correlated with the proximity of myeloma cells, while similar hybrid cells were generated in myeloma cell–osteoclast cocultures indicating that hybrid cells can originate through fusion between myeloma cells and osteoclasts [6]. These data suggest that we may have underestimated the direct role of myeloma cells in bone resorption. In an attempt to better clarify this role, Silvestris et al. published in this issue of Leukemia Research that malignant plasma cells from U-266, RPMI 8226 and MCC-2 myeloma cell lines are able to exert an erosing activity on both calcium phosphate and dentin discs in vitro, resembling the inorganic and organic bone, respectively [7]. Furthermore, both primary myeloma cells and plasma cell lines express CTR-2, the widespread isoform of CTR, at higher intensity compared to plasma cells of monoclonal gammopathy of undetermined significance and control cell lines. CTR activation by CT was able to enhance both cAMP and Ca++ flow and subsequently activate protein kinase A and protein kinase C pathways in malignant plasma cells as in normal osteoclasts, leading to inhibition of their bone resorption function. The inhibition of the formation of erosive lacunae made by malignant plasma cells in the presence of CT supports an osteoclast functional differentiation of malignant plasma cells in vitro [7]. These in vitro results suggest that the activation of CTR by CT could inhibit bone resorption produced by both osteoclasts and myeloma cells. However, this has not been translated to a beneficial effect of CT in the management of bone disease of myeloma patients. Although CT produced an increase in trabecular bone volume, cortical thickness, osteoid volume and osteoid seam thickness index and reduced the osteoclast resorption surface in 11 MM patients [8], it did not reduce skeletal related events in other studies [9], possibly due to the down regulation of CTR expression. Current management of myeloma bone disease includes the use of bisphosphonates that are potent osteoclast
522
Editorial / Leukemia Research 32 (2008) 521–522
inhibitors. Novel anti-myeloma agents, such as proteasome inhibitors and immunomodulatory drugs seem to reduce bone resorption and possibly increase bone formation in these patients [10]. The knowledge that a subset of myeloma cells may also have osteoclast-like activity is important as it may reveal novel pathways for the development of new anti-myeloma agents. Furthermore, it will help us to better understand the biology of myeloma bone disease as we know that there are patients who show a tumor reduction due to anti-myeloma therapy, i.e. they achieve a reduction in paraprotein levels and plasma cell infiltration of the bone marrow, but they continue to develop new lytic lesions. A subset of myeloma cells with osteoclast-like activity that is resistant to the administered therapy may be probably responsible for such a phenomenon. Furthermore, the possibility that malignant plasma cells corrupt host cells by the transfer of malignant DNA, producing hybrid cells may have been undervalued in myeloma research to-date. However, the osteoclast-like activity of all or a subset of myeloma cells has to be confirmed in myeloma patients. The paper of Silvestris et al. drives researchers of myeloma bone disease to investigate this field also. Acknowledgements There is nothing to acknowledge for this Editorial. References [1] Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management. Ann Oncol 2005;16:1223–31. [2] Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J, et al. Soluble receptor activator of nuclear factor kappaB ligandosteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003;102:1064–9. [3] Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy Jr JD. Antibody-based inhibition of DKK1 suppresses tumor-induced
[4]
[5]
[6]
[7]
[8]
[9]
[10]
bone resorption and multiple myeloma growth in vivo. Blood 2007;109:2106–11. Calvani N, Cafforio P, Silvestris F, Dammacco F. Functional osteoclastlike transformation of cultured human myeloma cell lines. Br J Haematol 2005;130:926–38. McDonald DF, Schofield BH, Prezioso EM, Adams VL, Frondoza CA, Trivedi SM, et al. Direct bone resorbing activity of murine myeloma cells. Cancer Lett 1983;19:119–24. Andersen TL, Boissy P, Sondergaard TE, Kupisiewicz K, Plesner T, Rasmussen T, et al. Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer-host partnership? J Pathol 2007;211:10–7. Silvestris F, Cafforio P, De Matteo M, Quatraro C, Dammacco F. Expression and function of the calcitonin receptor by myeloma cells in their osteoclast-like activity in vitro. Leukemia Res 2008;32: 611–23. Rico H, Hernandez ER, Diaz-Mediavilla J, Alvarez A, Martinez R, Espinos D. Treatment of multiple myeloma with nasal spray calcitonin: a histomorphometric and biochemical study. Bone Miner 1990;8:231–7. Bataille R, Tenoudji-Cohen M, Rossi JF. Multiple myeloma: optimal use of salmon calcitonin in the management of myeloma osteoclastic bone disease. Br J Haematol 1983;53:170–1. Terpos E, Dimopoulos MA, Sezer O. The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma. Leukemia 2007;21:1875–84.
Evangelos Terpos a,b,∗ Department of Hematology and Medical Research, 251 General Air Force Hospital, Athens, Greece b Department of Hematology, Faculty of Medicine Imperial College London, London, UK a
∗ Correspondence
address: Department of Hematology and Medical Research, 251 General Air Force Hospital, 3 Kanellopoulou Street, GR-11525, Athens, Greece. Tel.: +30 210 7463803; fax: +30 210 7464676. E-mail addresses: [email protected], [email protected] 23 August 2007 Available online 3 October 2007