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(American Journal of Pathology. 2004;165:869-878.)
© 2004 American Society for Investigative Pathology

Multifunctional Role of Matrix Metalloproteinases in Multiple Myeloma

A Study in the 5T2MM Mouse Model

Els Van Valckenborgh*, Peter I. Croucher{dagger}, Hendrik De Raeve{ddagger}, Chris Carron§, Evy De Leenheer*{dagger}, Sylvia Blacher, Laetitia Devy, Agnès Noël, Elke De Bruyne*, Kewal Asosingh*, Ivan Van Riet*, Ben Van Camp* and Karin Vanderkerken*

From the Department of Hematology and Immunology,* Vrije Universiteit Brussel, Brussels, Belgium; the Department of Pathology,{ddagger} University of Antwerp, Edegem, Belgium; the Laboratory of Biology of Tumour and Development, University of Liège, Liège, Belgium; the Division of Clinical Sciences (South),{dagger} University of Sheffield Medical School, Sheffield, United Kingdom; and Pfizer,§ Saint Louis, Missouri

Matrix metalloproteinases (MMPs) are known to play a role in cell growth, invasion, angiogenesis, metastasis, and bone degradation, all important events in the pathogenesis of cancer. Multiple myeloma is a B-cell cancer characterized by the proliferation of malignant plasma cells in the bone marrow, increased angiogenesis, and the development of osteolytic bone disease. The role of MMPs in the development of multiple myeloma is poorly understood. Using SC-964, a potent inhibitor of several MMPs (MMP-2, -3, -8, -9, and -13), we investigated the role of MMPs in the 5T2MM murine model. Reverse transcriptase-polymerase chain reaction demonstrated the presence of mRNA for MMP-2, -8, -9, and -13 in 5T2MM-diseased bone marrow. Mice bearing 5T2MM cells were given access to food containing SC-964. The concentration of SC-964 measured in the plasma of mice after 11 days of treatment was able to inhibit MMP-9 activity in gelatin zymography. Treatment of 5T2MM-bearing mice resulted in a significant reduction in tumor burden, a significant decrease in angiogenesis, and partially protective effect against the development of osteolytic bone disease. The direct role of MMPs in these different processes was confirmed by in vitro experiments. All these results support the multifunctional role of MMPs in the development of multiple myeloma.




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