title: Matrix metalloproteinases and lysosomal cysteine proteases in osteoclasts contribute to bone resorption through distinct modes of action.
abstract: The effects of inhibitors of matrix metalloproteinases (MMPs) and lysosomal cysteine proteases on osteoclastic pit formation in dentine slices were investigated. A nonspecific cysteine protease inhibitor, E-64, inhibited pit formation on naked slices in a concentration-dependent manner, and at 10 microM E-64 reduced the pit volume by 70%. However, up to 10 microM of the MMP inhibitor, BB-94, did not show any inhibition of pit formation. On the other hand, on slices coated with reconstituted basement membrane, both BB-94 and E-64 at 10 microM showed a marked decrease in pit volume by 73% and 68%, respectively. By a combination of treatment with both BB-94 and E-64, pit formation could be completely suppressed. These results suggest that MMPs are necessary for the migration of precursor and/or immature osteoclasts to bone surface through basement membranes, while cysteine proteases are essential for the osteoclastic degradation of bone collagen.
authors.affiliation: Takarazuka Research Institute, Novartis Pharma K.K., 10-66 Miyuki-cho, Takarazuka, 665-8666, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inui
authors.forename: O
authors.initials: O
authors.lastname: Ishibashi
authors.forename: Y
authors.initials: Y
authors.lastname: Origane
authors.forename: K
authors.initials: K
authors.lastname: Fujimori
authors.forename: T
authors.initials: T
authors.lastname: Kokubo
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D001483:Base Sequence; D001862:Bone Resorption; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D017931:DNA Primers; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008247:Lysosomes / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D003546:Cysteine Endopeptidases; D008666:Metalloendopeptidases; D007930:Leucine; C024974:E 64