Matrix metalloproteinase inhibitors reduce collagen gel contraction and alpha-smooth muscle actin expression by periodontal ligament cells.
OBJECTIVE
Orthodontic tooth movement requires remodeling of the periodontal tissues. The matrix metalloproteinases (MMPs) degrade the extracellular matrix components of the periodontal ligament, while the tissue inhibitors of metalloproteinases (TIMPs) control their activity. Synthetic MMP inhibitors have been developed to inhibit MMP activity. In this study, periodontal ligament cells in contracting collagen gels served as a model for enhanced periodontal remodeling. The effect of MMP inhibitors on gel contraction and on MMP and TIMP expression was analyzed.


METHODS
Human periodontal ligament cells were cultured in three-dimensional collagen gels and incubated with the MMP inhibitors BB94, CMT-3, doxycycline and Ilomastat. Gel contraction was determined using consecutive photographs. The relative amounts of MMPs and TIMPs were analyzed using substrate zymography and mRNA expression using quantitative polyermase chain reaction.


RESULTS
All MMP inhibitors reduced MMP activity to about 20% of the control activity. They all reduced contraction, but CMT-3 and doxycycline had the strongest effect. These inhibitors also reduced MMP-2, MMP-3 and alpha-smooth muscle actin mRNA expression. The expression of MMP-1 mRNA seemed to be increased by CMT-3. No effects were found on the amounts of MMPs and TIMPs.


CONCLUSIONS
Synthetic MMP inhibitors strongly reduced gel contraction by periodontal ligament cells. This was primarily caused by an inhibitory effect on MMP activity, which reduces matrix remodeling. In addition, alpha-smooth muscle actin expression was reduced by CMT-3 and doxycycline, which limits the contractile activity of the fibroblasts.
Bildt
M M
MM
Orthodontics & Oral Biology, Radboud University Nijmegen Medical Centre, Philips van Leydenlaan 25, Nijmegen, The Netherlands.
Bloemen
M
M
Kuijpers-Jagtman
A M
AM
Von den Hoff
J W
JW
D000199:Actins / Q000096:biosynthesis / Q000187:drug effects; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects; D003799:Dental Stress Analysis; D004318:Doxycycline / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005782:Gels; D006801:Humans; D006877:Hydroxamic Acids; D007211:Indoles / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D010513:Periodontal Ligament / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D013754:Tetracyclines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis; D014087:Tooth Movement Techniques
D000199:Actins; D005782:Gels; D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013754:Tetracyclines; D013876:Thiophenes; D019714:Tissue Inhibitor of Metalloproteinases; C117155:tetracycline CMT-3; D010649:Phenylalanine; D003094:Collagen; C080985:batimastat; D020782:Matrix Metalloproteinases; C119203:ilomastat; D004318:Doxycycline