title: Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline.
abstract: Collagenases or matrix metalloproteinases (MMPs) have been shown to play an important role in the matrix degradation cascade associated with Achilles tendon rupture and disease. The goal of this study was to examine the effects of daily administration of doxycycline (Doxy) through oral gavage on MMP activity and on the repair quality of Achilles tendons in vivo. Our findings indicate that Achilles tendon transection resulted in increasing MMP-8 activity from 2 to 6 weeks post-injury, with peak increases in activity occurring at 4 weeks post-injury. Doxy adiministration at clinically relevant serum concentrations was found to significantly inhibit MMP activity after continuous treatment for 4 weeks, but not for continuous administration for shorter durations (96 h or 2 weeks). Extended doxy administration was also associated with improved collagen fibril organization, and enhanced biomechanical properties (stiffness, ultimate tensile strength, maximum load to failure, and elastic toughness). Our findings indicate that a temporal delay exists between Achilles tendon transection and associated increases in MMP-8 activity in situ. Our findings suggest that inhibition of MMP-8 at its peak activity levels ameliorates fibrosis development and improves biomechanical properties of the Achilles tendon.
authors.affiliation: Orthopaedic Research Lab, The Feinstein Institute for Medical Research, Manhasset, New York; Georgetown University Hospital, Washington, District of Columbia.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Kessler
authors.forename: Jerome
authors.initials: J
authors.lastname: Barr
authors.forename: Robert
authors.initials: R
authors.lastname: Greenwald
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Lane
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Dines
authors.forename: David M
authors.initials: DM
authors.lastname: Dines
authors.forename: Mark C
authors.initials: MC
authors.lastname: Drakos
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Grande
authors.forename: Nadeen O
authors.initials: NO
authors.lastname: Chahine
mesh_terms: D000125:Achilles Tendon / Q000187:drug effects / Q000293:injuries / Q000601:surgery*; D000284:Administration, Oral; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004318:Doxycycline / Q000008:administration & dosage*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013708:Tendon Injuries / Q000188:drug therapy*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; D020784:Matrix Metalloproteinase 8; D004318:Doxycycline
keywords: achilles tendon; doxycycline; matrix metalloproteinase; tendon rupture and repair