Antisense inhibition of macrophage inflammatory protein 1-α blocks bone destruction in a model of myeloma bone disease
Sun Jin Choi, Yasuo Oba, Yair Gazitt, Melissa Alsina, Jose Cruz, Judith Anderson, G. David Roodman
Sun Jin Choi, Yasuo Oba, Yair Gazitt, Melissa Alsina, Jose Cruz, Judith Anderson, G. David Roodman
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Antisense inhibition of macrophage inflammatory protein 1-α blocks bone destruction in a model of myeloma bone disease

Abstract

We recently identified macrophage inflammatory protein 1-α (MIP-1α) as a factor produced by multiple myeloma (MM) cells that may be responsible for the bone destruction in MM (1). To investigate the role of MIP-1α in MM bone disease in vivo, the human MM–derived cell line ARH was stably transfected with an antisense construct to MIP-1α (AS-ARH) and tested for its capacity to induce MM bone disease in SCID mice. Human MIP-1α levels in marrow plasma from AS-ARH mice were markedly decreased compared with controls treated with ARH cells transfected with empty vector (EV-ARH). Mice treated with AS-ARH cells lived longer than controls and, unlike the controls, they showed no radiologically identifiable lytic lesions. Histomorphometric analysis demonstrated that osteoclasts (OCLs) per square millimeter of bone and OCLs per millimeter of bone surface of AS-ARH mice were significantly less than in EV-ARH mice, and the percentage of tumors per total bone area was also significantly decreased. AS-ARH cells demonstrated decreased adherence to marrow stromal cells, due to reduced expression of the α5β1 integrin and diminished homing capacity and survival. These data support an important role for MIP-1α in cell homing, survival, and bone destruction in MM.

Authors

Sun Jin Choi, Yasuo Oba, Yair Gazitt, Melissa Alsina, Jose Cruz, Judith Anderson, G. David Roodman

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Survival of SCID mice implanted with WT-, ET-, or AS-ARH cells and expre...
Survival of SCID mice implanted with WT-, ET-, or AS-ARH cells and expression of MIP-1α in vivo. WT-, EV-, and AS-ARH cells were infused intravenously into SCID mice (n = 10 per group) as described in Methods and were sacrificed when they became paraplegic. Femurs and vertebrae were then removed and bone marrow plasma obtained by flushing the bones with 1 ml of serum-free αMEM. Expression levels of hMIP-1α (a) and human IgG (b) were measured with ELISA kits. hMIP-1α expression in mice implanted with AS-ARH cells was reduced to almost undetectable levels. Human IgG levels, which are indicators of tumor burden, were significantly reduced in AS-ARH mice compared with WT- or EV-ARH mice, but were still detectable (0.1–1 μg/ml). Similar results were seen in three independent experiments (*P < 0.0001).