Matrix metalloproteinase inhibitors prevent a decrease in the mechanical properties of stress-deprived tendons: an in vitro experimental study.
BACKGROUND
An increase in matrix metalloproteinases (MMPs) and the resulting degradation of the extracellular matrix have been implicated in the pathogenesis of tendinopathy. Studies have documented the beneficial effects of MMP inhibitors used to treat pathologic conditions in which MMP activity has had a negative effect on connective tissues.


OBJECTIVE
Matrix metalloproteinase inhibitors will prevent the decrease in material properties associated with tendon stress deprivation by inhibiting MMP activity.


METHODS
Controlled laboratory study.


METHODS
Rat tail tendons were subjected to 7 days of in vitro stress deprivation with and without the addition of 1 of 2 broad-spectrum MMP inhibitors (doxycycline and ilomastat). The material properties (ultimate tensile stress, strain, and tensile modulus) of the tendons were compared with each other and with fresh control tendons. In addition, tendons from each group were evaluated for MMP-13 messenger RNA expression, MMP-13 protein synthesis, MMP-13 activity, and pericellular matrix morphology.


RESULTS
Both MMP inhibitors resulted in a statistically significant reduction in MMP activity in 7 day stress-deprived tendons when compared with nontreated, stress-deprived tendons. Similarly, tendons treated with either ilomastat or doxycycline had significantly improved material properties. MMP-13 messenger RNA expression and protein synthesis were not significantly affected by either MMP inhibitor. Both MMP inhibitors were able to maintain the integrity of the pericellular matrix when compared with nontreated, stress-deprived tendons.


CONCLUSIONS
Matrix metalloproteinase inhibitors prevented the activation of MMP-13 and significantly inhibited pericellular matrix degeneration and the loss of material properties associated with stress deprivation.


CONCLUSIONS
Matrix metalloproteinase inhibitors may play a supportive role in the treatment of tendinopathy by limiting the MMP-mediated degradation of the extracellular matrix.
Arnoczky
Steven P
SP
Laboratory for Comparative Orthopaedic Research, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. arnoczky@cvm.msu.edu
Lavagnino
Michael
M
Egerbacher
Monika
M
Caballero
Oscar
O
Gardner
Keri
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects*; D006877:Hydroxamic Acids; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D052256:Tendinopathy / Q000188:drug therapy*; D013710:Tendons / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D053509:Matrix Metalloproteinase 13; C119203:ilomastat; D004318:Doxycycline