scholarly journals Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2195-2202 ◽  
Author(s):  
Masahiro Abe ◽  
Kenji Hiura ◽  
Javier Wilde ◽  
Keiji Moriyama ◽  
Toshihiro Hashimoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Abstract Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)–1α and MIP-1β, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1α and MIP-1β correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1α and MIP-1β. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1α and MIP-1β, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1α and MIP-1β induce expression of receptor activator of nuclear factor-κB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1α and MIP-1β may be major osteoclast-activating factors produced by MM cells.

scholarly journals Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2195-2202 ◽  
Author(s):  
Masahiro Abe ◽  
Kenji Hiura ◽  
Javier Wilde ◽  
Keiji Moriyama ◽  
Toshihiro Hashimoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)–1α and MIP-1β, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1α and MIP-1β correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1α and MIP-1β. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1α and MIP-1β, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1α and MIP-1β induce expression of receptor activator of nuclear factor-κB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1α and MIP-1β may be major osteoclast-activating factors produced by MM cells.

Macrophage inflammatory protein-1α is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor κB ligand

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3349-3353 ◽  
Author(s):  
Je-Ho Han ◽  
Sun Jin Choi ◽  
Noriyoshi Kurihara ◽  
Masanori Koide ◽  
Yasuo Oba ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Nuclear Factor Κb ◽  
Marrow Stromal Cells ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Myeloma Cells ◽  
Parathyroid Hormone Related Protein ◽  
Inflammatory Protein ◽  
Receptor Activator ◽  
Macrophage Inflammatory Protein

A complementary DNA expression library derived from marrow samples from myeloma patients was recently screened and human macrophage inflammatory protein-1α (hMIP-1α) was identified as an osteoclastogenic factor expressed in these samples. hMIP-1α enhanced osteoclast (OCL) formation in human marrow cultures and by highly purified OCL precursors in a dose-dependent manner (5-200 pg/mL). Furthermore, hMIP-1α enhanced OCL formation induced by human interleukin-6 (IL-6), which is produced by marrow stromal cells when they interact with myeloma cells. hMIP-1α also enhanced OCL formation induced by parathyroid hormone-related protein (PTHrP) and receptor activator of nuclear factor κB ligand (RANKL), factors also implicated in myeloma bone disease. Time-course studies revealed that the hMIP-1α acted during the last 2 weeks of the 3-week culture period. Reverse transcription–polymerase chain reaction analysis showed that the chemokine receptors for hMIP-1α (CCR1 and CCR5) were expressed by human bone marrow and highly purified early OCL precursors. Furthermore, hMIP-1α did not increase expression of RANKL. These data demonstrate that hMIP-1α is an osteoclastogenic factor that appears to act directly on human OCL progenitors and acts at the later stages of OCL differentiation. These data further suggest that in patients with myeloma, MIP-1α produced by myeloma cells, in combination with RANKL and IL-6 that are produced by marrow stromal cells in response to myeloma cells, enhances OCL formation through their combined effects on OCL precursors.

Cell–cell contact between marrow stromal cells and myeloma cells via VCAM-1 and α4β1-integrin enhances production of osteoclast-stimulating activity

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1953-1960 ◽  
Author(s):  
Toshimi Michigami ◽  
Nobuaki Shimizu ◽  
Paul J. Williams ◽  
Maria Niewolna ◽  
Sarah L. Dallas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Bone Destruction ◽  
Marrow Stromal Cells ◽  
Cell Contact ◽  
Tartrate Resistant Acid Phosphatase ◽  
Myeloma Cells ◽  
Bone Resorbing Activity

Abstract Myeloma is a unique hematologic malignancy that exclusively homes in the bone marrow and induces massive osteoclastic bone destruction presumably by producing cytokines that promote the differentiation of the hematopoietic progenitors to osteoclasts (osteoclastogenesis). It is recognized that neighboring bone marrow stromal cells influence the expression of the malignant phenotype in myeloma cells. This study examined the role of the interactions between myeloma cells and neighboring stromal cells in the production of osteoclastogenic factors to elucidate the mechanism underlying extensive osteoclastic bone destruction. A murine myeloma cell line 5TGM1, which causes severe osteolysis, expresses α4β1-integrin and tightly adheres to the mouse marrow stromal cell line ST2, which expresses the vascular cell adhesion molecule-1 (VCAM-1), a ligand for α4β1-integrin. Co-cultures of 5TGM1 with primary bone marrow cells generated tartrate-resistant acid phosphatase-positive multinucleated bone-resorbing osteoclasts. Co-cultures of 5TGM1 with ST2 showed increased production of bone-resorbing activity and neutralizing antibodies against VCAM-1 or α4β1-integrin inhibited this. The 5TGM1 cells contacting recombinant VCAM-1 produced increased osteoclastogenic and bone-resorbing activity. The activity was not blocked by the neutralizing antibody to known osteoclastogenic cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor, or parathyroid hormone-related peptide. These data suggest that myeloma cells are responsible for producing osteoclastogenic activity and that establishment of direct contact with marrow stromal cells via α4β1-integrin/VCAM-1 increases the production of this activity by myeloma cells. They also suggest that the presence of stromal cells may provide a microenvironment that allows exclusive colonization of myeloma cells in the bone marrow.

SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-κB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 2130-2138 ◽  
Author(s):  
Rentian Feng ◽  
Gülsüm Anderson ◽  
Guozhi Xiao ◽  
Gary Elliott ◽  
Lorenzo Leoni ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Bone Resorption ◽  
Bone Destruction ◽  
Structural Analog ◽  
Myeloma Cell ◽  
Osteoclast Formation ◽  
Myeloma Cells ◽  
Osteoclast Activity ◽  
Multiple Myeloma Cell

Abstract Multiple myeloma is characterized by increased osteoclast activity that results in bone destruction and lytic lesions. With the prolonged overall patient survival achieved by new treatment modalities, additional drugs are required to inhibit bone destruction. We focused on a novel and more potent structural analog of the nonsteroidal anti-inflammatory drug etodolac, known as SDX-308, and its effects on osteoclastogenesis and multiple myeloma cells. SDX-101 is another structural analog of etodolac that is already used in clinical trials for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Compared with SDX-101, a 10-fold lower concentration of SDX-308 induced potent (60%-80%) inhibition of osteoclast formation, and a 10- to 100-fold lower concentration inhibited multiple myeloma cell proliferation. Bone resorption was completely inhibited by SDX-308, as determined in dentin-based bone resorption assays. SDX-308 decreased constitutive and RANKL-stimulated NF-κB activation and osteoclast formation in an osteoclast cellular model, RAW 264.7. SDX-308 effectively suppressed TNF-α–induced IKK-γ and IκB-α phosphorylation and degradation and subsequent NF-κB activation in human multiple myeloma cells. These results indicate that SDX-308 effectively inhibits multiple myeloma cell proliferation and osteoclast activity, potentially by controlling NF-κB activation signaling. We propose that SDX-308 is a promising therapeutic candidate to inhibit multiple myeloma growth and osteoclast activity and that it should receive attention for further study.

Cell–cell contact between marrow stromal cells and myeloma cells via VCAM-1 and α4β1-integrin enhances production of osteoclast-stimulating activity

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1953-1960 ◽  
Author(s):  
Toshimi Michigami ◽  
Nobuaki Shimizu ◽  
Paul J. Williams ◽  
Maria Niewolna ◽  
Sarah L. Dallas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Bone Destruction ◽  
Marrow Stromal Cells ◽  
Cell Contact ◽  
Tartrate Resistant Acid Phosphatase ◽  
Myeloma Cells ◽  
Bone Resorbing Activity

Myeloma is a unique hematologic malignancy that exclusively homes in the bone marrow and induces massive osteoclastic bone destruction presumably by producing cytokines that promote the differentiation of the hematopoietic progenitors to osteoclasts (osteoclastogenesis). It is recognized that neighboring bone marrow stromal cells influence the expression of the malignant phenotype in myeloma cells. This study examined the role of the interactions between myeloma cells and neighboring stromal cells in the production of osteoclastogenic factors to elucidate the mechanism underlying extensive osteoclastic bone destruction. A murine myeloma cell line 5TGM1, which causes severe osteolysis, expresses α4β1-integrin and tightly adheres to the mouse marrow stromal cell line ST2, which expresses the vascular cell adhesion molecule-1 (VCAM-1), a ligand for α4β1-integrin. Co-cultures of 5TGM1 with primary bone marrow cells generated tartrate-resistant acid phosphatase-positive multinucleated bone-resorbing osteoclasts. Co-cultures of 5TGM1 with ST2 showed increased production of bone-resorbing activity and neutralizing antibodies against VCAM-1 or α4β1-integrin inhibited this. The 5TGM1 cells contacting recombinant VCAM-1 produced increased osteoclastogenic and bone-resorbing activity. The activity was not blocked by the neutralizing antibody to known osteoclastogenic cytokines including interleukin (IL)-1, IL-6, tumor necrosis factor, or parathyroid hormone-related peptide. These data suggest that myeloma cells are responsible for producing osteoclastogenic activity and that establishment of direct contact with marrow stromal cells via α4β1-integrin/VCAM-1 increases the production of this activity by myeloma cells. They also suggest that the presence of stromal cells may provide a microenvironment that allows exclusive colonization of myeloma cells in the bone marrow.

Macrophage inflammatory protein 1-alpha (MIP-1α) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3568-3573 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Margarete Gries ◽  
Martin Janz ◽  
Ralf Bargou ◽  
Bernd Dörken ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Bone Destruction ◽  
Mitogen Activated Protein Kinase ◽  
Bone Lesions ◽  
Inflammatory Protein ◽  
Mitogen Activated Protein ◽  
And Migration ◽  
Macrophage Inflammatory Protein

Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1α) is crucially involved in the development of osteolytic bone lesions in multiple myeloma (MM). The current study was designed to determine the direct effects of MIP-1α on MM cells. Thus, we were able to demonstrate that MIP-1α acts as a potent growth, survival, and chemotactic factor in MM cells. MIP-1α–induced signaling involved activation of the AKT/protein kinase B (PKB) and the mitogen-activated protein kinase (MAPK) pathway. In addition, inhibition of AKT activation by phosphatidylinositol 3- kinase (PI3-K) inhibitors did not influence MAPK activation, suggesting that there is no cross talk between MIP-1α–dependent activation of the PI3-K/AKT and extracellular-regulated kinase (ERK) pathway. Our data suggest that besides its role in development of osteolytic bone destruction, MIP-1α also directly affects cell signaling pathways mediating growth, survival, and migration in MM cells and provide evidence that MIP-1α might play a pivotal role in the pathogenesis of MM.

Bortezomib Protects Osteoblasts from Glucocorticoid-Induced Damage, and Enhances Glucocorticoid-Induced Toxicity Against Osteoclasts and Myeloma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3523-3523
Author(s):  
Kent Soe ◽  
Thomas L. Andersen ◽  
Katarzyna Kupisiewicz ◽  
Torben Plesner ◽  
Jean-Marie Delaisse
Keyword(s):  
Multiple Myeloma ◽  
Bone Repair ◽  
Plasma Cells ◽  
Bone Cells ◽  
Negative Impact ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
The Impact ◽  
Human Osteoclasts

Abstract Introduction: Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow, and leads most often to bone destruction by osteoclasts and prevention of bone repair by osteoblasts. Bortezomib and glucocorticoids are both powerful anti-myeloma drugs that are used for killing malignant plasma cells in the patients. Furthermore bortezomib has direct anti-osteoclastic and pro-osteoblastic properties that may contribute to bone protection in multiple myeloma, while glucocorticoids have more ambiguous effects on these bone cells and are clearly anti-osteoblastic. Recent clinical trials based on the combination of bortezomib and glucocorticoids drew the attention on the very promising anti-myeloma efficiency of this combination. However, the bone cell response of this combination has not been tested. In order to address this question, we performed an in vitro study, and importantly adapted our in vitro model to mimic the pharmacokinetics of bortezomib and glucocorticoid in the patients. Methods: Myeloma cell lines, primary human osteoclasts and osteoblast-like cells (MC3T3) were pulse-treated or not with clinically relevant doses of bortezomib (12.5, 25 or 50 nM) for 3 hours. Subsequently, the cells were exposed during a 3-day culture to 1.6 μM prednisolone which approximately corresponds to a dose of 50 mg prednisolone in a patient. The impact of the treatment on the cells was determined by survival, activity and gene expression. Results: Bortezomib as a single treatment was very efficient in killing sensitive myeloma cells (OPM2) whereas the more resistant cells (U266) were more efficiently killed in combination with prednisolone. The release of TRAP from primary human osteoclasts, a marker of osteoclastic activation, was strongly inhibited by bortezomib treatment alone, but only in combination with prednisolone did it result in killing of osteoclasts. Survival of osteoblast like cells was uninfluenced by treatment with bortezomib alone. In contrast, as shown previously, prednisolone strongly reduced osteoblast survival. Most importantly however, a 3 hr pre-treatment with bortezomib protected the osteoblasts against the detrimental effects of glucocorticoids. Ongoing investigations by Q-PCR indicate that important markers of osteoblast maturation remain high if the osteoblasts were pre-treated with bortezomib prior to prednisolone exposure. Conclusion: Our study demonstrates in conditions relevant to treatment of myeloma patients, that combining bortezomib and glucocorticoids has a direct synergistic effect against myeloma cells and osteoclasts, and that bortezomib protects directly osteoblasts from the negative impact of glucocorticoids. Thus, the combination of bortezomib and glucocorticoids is not only a powerful treatment of multiple myeloma itself, but also shows promise for treating myeloma bone disease.

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1α) correlate with the extent of bone disease and survival in patients with multiple myeloma

2003 ◽  
Vol 123 (1) ◽  
pp. 106-109 ◽  
Author(s):  
Evangelos Terpos ◽  
Marianna Politou ◽  
Richard Szydlo ◽  
John M. Goldman ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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