MMP inhibition and downregulation by bisphosphonates.
Bisphosphonates are a group of drugs capable of inhibiting bone resorption, and are thus used for the treatment of bone diseases, such as Paget's disease, osteoporosis, and for bone metastases of malignant tumors. Their primary cellular target is considered to be the osteoclast. The molecular mechanisms responsible for the downregulation of bone resorption by bisphosphonates have remain unclear. We have discovered that various matrix metalloproteinases (MMPs) are inhibited in vitro by several bisphosphonates. This novel finding may, in part, explain the efficacy of bisphosphonates in their current indications in humans. In enzyme activity tests using purified and recombinant enzymes, we have observed the inhibition of MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 by clondronate, alendronate, pamidronate, zolendronate, nedrinate, and clodrinate. The IC50s range from 50 to 150 microM. We have also shown that clodronate can downregulate the expression of MT1-MMP protein and mRNA in several cell lines. Additionally, several bisphosphonates decrease the degree of invasion of malignant melanoma (C8161) and fibrosarcoma (HT1080) cells through artificial basement membrane (Matrigel) in cell cultures at IC50s of 50-150 microM and below. Having low toxicity and proven to be well tolerated after several years in human use, bisphosphonates have the potential to become one of the main MMP-inhibitors for MMP-related human soft and hard tissue-destructive diseases in the near future.
Department of Oral and Maxillofacial Surgery, University of Helsinki, Finland. olli.teronen@helsinki.fi
O
O
Teronen
P
P
Heikkilä
Y T
YT
Konttinen
M
M
Laitinen
T
T
Salo
R
R
Hanemaaijer
A
A
Teronen
P
P
Maisi
T
T
Sorsa
D019386:Alendronate / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001826:Body Fluids / Q000201:enzymology*; D017364:Collagenases / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology* / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008666:Metalloendopeptidases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D000077268:Pamidronate; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004164:Diphosphonates; D011480:Protease Inhibitors; D017364:Collagenases; D008666:Metalloendopeptidases; D000077268:Pamidronate; D019386:Alendronate