A selective inhibitor of matrix metalloproteinases inhibits the migration of isolated osteoclasts by increasing the life span of podosomes.
The osteoclast is a unique cell that cycles between bone resorption and migration. In this study, we used KB-R7785, an inhibitor of matrix metalloproteinases (MMPs), to investigate the role of MMPs in this cycle. Osteoclasts prepared from neonatal rabbits were processed to measure: (1) migration on hydroxyapatite (HA)-coated dishes, (2) the formation of an actin band, which is a large collection of podosomes, (3) the life span of podosomes, and (4) lacunar resorption on ivory slices. KB-R7785 significantly decreased the area of the tracks formed by osteoclasts on HA-coated dishes. The percentage of actin/podosome band formation, expressed as: (total length of the actin band/circumference of the osteoclast) x 100, was significantly increased after the addition of KB-R7785, which implies that podosome disassembly in osteoclasts was decreased by the inhibition of MMPs. Time-lapse cinemicrography demonstrated that the addition of KB-R7785 increased the life span of podosomes. Several indexes (number of resorption pits, total resorption area, and mean resorption area) of osteoclast resorption activity were significantly decreased by KB-R7785, while the average depth of resorption was increased. These results indicate that decreased podosome disassembly caused by an MMP inhibitor suppresses the migration of osteoclasts and, ultimately, inhibits osteoclastic bone resorption.
Goto
Tetsuya
T
Department of Oral Anatomy, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580, Japan.
Maeda
Hidefumi
H
Tanaka
Teruo
T
D000199:Actins / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D015394:Molecular Structure; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011817:Rabbits
D000199:Actins; D015853:Cysteine Proteinase Inhibitors; D006877:Hydroxamic Acids; C107086:KB R7785; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases; D007930:Leucine; C024974:E 64; D005998:Glycine