Regulation of MMP-9 (gelatinase B) in activated human monocyte/macrophages by two different types of bisphosphonates.
Metalloproteinases (MMP), particularly MMP-9 produced by the intratumor monocyte/macrophages, play an important role in tumor invasion and metastases. Recent clinical trials in patients with primary breast cancer suggest that bisphosphonates (BP), above all clodronate, may reduce bone metastases. The aim of the present study was to evaluate whether the effects of BPs on cancer dissemination include inhibition of MMP-9 production in human monocyte/macrophages. The effects of clodronate and pamidronate on the MMP-9 expression in and secretion from stimulated human monocyte/macrophages were measured using quantitative reverse transcriptase - polymerase chain reaction (RT-PCR) and enzyme-linked immunoadsorbent assay (ELISA), respectively. The MMP-9 mRNA levels remained relatively stable in the presence of clodronate. In contrast, pamidronate at 30 microM-300 microM increased the mRNA levels 5- to 10-fold. MMP-9 secretion was dose-dependently down-regulated by clodronate whereas pamidronate at 30 microM induced a 50% increase on MMP-9 secretion (p < 0.05), followed by a down-regulation at higher concentrations. The results suggest that MMP-9 is differentially regulated at mRNA and enzyme protein level by BPs, which affect ATP-dependent intracellular enzymes (clodronate) or post-translational modification of GTPases (pamidronate). These findings may have implications for the therapeutic use of these compounds.
Valleala
H
H
Department of Medicine, Helsinki University Central Hospital, Kasarmikatu 11-13 FIN-00130, Helsinki, Finland. heikki.valleala@hus.fi
Hanemaaijer
R
R
Mandelin
J
J
Salminen
A
A
Teronen
O
O
Mönkkönen
J
J
Konttinen
Y T
YT
D004002:Clodronic Acid / Q000494:pharmacology*; D017077:Culture Media, Conditioned; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D000077268:Pamidronate; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017077:Culture Media, Conditioned; D004164:Diphosphonates; D012333:RNA, Messenger; D004002:Clodronic Acid; D020780:Matrix Metalloproteinase 9; D000077268:Pamidronate