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 language | English (US) |
|---|---|
| Pages (from-to) | 311-319 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 102 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 1 2003 |
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ASJC Scopus subject areas
- Hematology
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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 journal › Article
}
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 -