Multifunctional role of matrix metalloproteinases in multiple myeloma: a study in the 5T2MM mouse model.
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.
Department Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
Els
E
Van Valckenborgh
Peter I
PI
Croucher
Hendrik
H
De Raeve
Chris
C
Carron
Evy
E
De Leenheer
Sylvia
S
Blacher
Laetitia
L
Devy
Agnès
A
Noël
Elke
E
De Bruyne
Kewal
K
Asosingh
Ivan
I
Van Riet
Ben
B
Van Camp
Karin
K
Vanderkerken
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001847:Bone Diseases / Q000201:enzymology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D004032:Diet; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020782:Matrix Metalloproteinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000098:blood supply / Q000201:enzymology* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000517:prevention & control; D010014:Osteolysis / Q000201:enzymology / Q000517:prevention & control; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism
D017304:Annexin A5; D004791:Enzyme Inhibitors; D020782:Matrix Metalloproteinases; D013936:Thymidine