Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease

Babatunde Oyajobi, Giovanni Franchin, Paul J. Williams, Donna Pulkrabek, Anjana Gupta, Steve Munoz, Barry Grubbs, Ming Zhao, Di Chen, Barbara Sherry, Gregory R. Mundy

Research output: Contribution to journalArticle

170 Citations (Scopus)

Abstract

Recent data have implicated macrophage inflammatory protein-1α (MIP-1α) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1α requires other factors such as receptor activator of nuclear factor-λB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1α antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1α on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1α (CHO/MIP-1α) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1α tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1α tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1α tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1α over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1α had no effect in RANK-/- mice. Together, these results establish that MIP-1α is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1α exerts a dual effect in myeloma, on osteoclasts, and tumor cells.

Original languageEnglish (US)
Pages (from-to)311-319
Number of pages9
JournalBlood
Volume102
Issue number1
DOIs
StatePublished - Jul 1 2003

Fingerprint

Macrophage Inflammatory Proteins
Osteolysis
Bone Diseases
Tumor Burden
Tumors
Bone
Bearings (structural)
Cricetulus
Ovary
Osteoclasts
Neoplasms
Multiple Myeloma
Bone and Bones
Cells
Paraproteins
Bone Development
Splenomegaly
Hypercalcemia
Cytoplasmic and Nuclear Receptors
Acid Phosphatase

ASJC Scopus subject areas

  • Hematology

Cite this

Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. / Oyajobi, Babatunde; Franchin, Giovanni; Williams, Paul J.; Pulkrabek, Donna; Gupta, Anjana; Munoz, Steve; Grubbs, Barry; Zhao, Ming; Chen, Di; Sherry, Barbara; Mundy, Gregory R.

In: Blood, Vol. 102, No. 1, 01.07.2003, p. 311-319.

Research output: Contribution to journalArticle

Oyajobi, B, Franchin, G, Williams, PJ, Pulkrabek, D, Gupta, A, Munoz, S, Grubbs, B, Zhao, M, Chen, D, Sherry, B & Mundy, GR 2003, 'Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease', Blood, vol. 102, no. 1, pp. 311-319. https://doi.org/10.1182/blood-2002-12-3905
Oyajobi, Babatunde ; Franchin, Giovanni ; Williams, Paul J. ; Pulkrabek, Donna ; Gupta, Anjana ; Munoz, Steve ; Grubbs, Barry ; Zhao, Ming ; Chen, Di ; Sherry, Barbara ; Mundy, Gregory R. / Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. In: Blood. 2003 ; Vol. 102, No. 1. pp. 311-319.
@article{db831fa8e74c4d70a12fec8629bd93dd,
title = "Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease",
abstract = "Recent data have implicated macrophage inflammatory protein-1α (MIP-1α) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1α requires other factors such as receptor activator of nuclear factor-λB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1α antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1α on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1α (CHO/MIP-1α) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1α tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1α tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1α tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1α over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1α had no effect in RANK-/- mice. Together, these results establish that MIP-1α is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1α exerts a dual effect in myeloma, on osteoclasts, and tumor cells.",
author = "Babatunde Oyajobi and Giovanni Franchin and Williams, {Paul J.} and Donna Pulkrabek and Anjana Gupta and Steve Munoz and Barry Grubbs and Ming Zhao and Di Chen and Barbara Sherry and Mundy, {Gregory R.}",
year = "2003",
month = "7",
day = "1",
doi = "10.1182/blood-2002-12-3905",
language = "English (US)",
volume = "102",
pages = "311--319",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "1",

}

TY - JOUR

T1 - Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease

AU - Oyajobi, Babatunde

AU - Franchin, Giovanni

AU - Williams, Paul J.

AU - Pulkrabek, Donna

AU - Gupta, Anjana

AU - Munoz, Steve

AU - Grubbs, Barry

AU - Zhao, Ming

AU - Chen, Di

AU - Sherry, Barbara

AU - Mundy, Gregory R.

PY - 2003/7/1

Y1 - 2003/7/1

N2 - Recent data have implicated macrophage inflammatory protein-1α (MIP-1α) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1α requires other factors such as receptor activator of nuclear factor-λB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1α antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1α on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1α (CHO/MIP-1α) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1α tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1α tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1α tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1α over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1α had no effect in RANK-/- mice. Together, these results establish that MIP-1α is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1α exerts a dual effect in myeloma, on osteoclasts, and tumor cells.

AB - Recent data have implicated macrophage inflammatory protein-1α (MIP-1α) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1α requires other factors such as receptor activator of nuclear factor-λB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1α antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1α on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1α (CHO/MIP-1α) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1α tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1α tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1α tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1α over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1α had no effect in RANK-/- mice. Together, these results establish that MIP-1α is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1α exerts a dual effect in myeloma, on osteoclasts, and tumor cells.

UR - http://www.scopus.com/inward/record.url?scp=0038579121&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038579121&partnerID=8YFLogxK

U2 - 10.1182/blood-2002-12-3905

DO - 10.1182/blood-2002-12-3905

M3 - Article

C2 - 12649140

AN - SCOPUS:0038579121

VL - 102

SP - 311

EP - 319

JO - Blood

JF - Blood

SN - 0006-4971

IS - 1

ER -