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. Keywords: achilles tendon; matrix metalloproteinase; doxycycline; tendon rupture and repair Achilles tendon tears are devastating injuries, and have unpredictable outcomes with respect to return to function.1,2 Collagenases or matrix metalloproteinases (MMPs) have been shown to play an important role in the enzymatic matrix degradation cascade associated with tendon injury and disease.3-6 Tendon degeneration is an active, cell-mediated process that may result from a failure to regulate specific MMP activities in response to repeated injury or mechanical strain. After tendon rupture, increased activity of MMPs and increased matrix turnover have been associated with further deterioration in the quality of the collagen network.7-13 Downregulation of tissue inhibitors of MMPs (TIMPS) is also associated with disregulation of the ratio of MMP to TIMP activity, and has been implicated in the pathogenesis of tendinopathy. [8][9][10][11][12][13][14][15][16] Tenocyte production of MMP-1 and -3 underscores the potential for non-lymphocyte mediated cytokine production of proteases inducing local matrix changes. 17 Tetracyclines, through a mechanism independent of their antibiotic effects, have been shown to substantially inhibit the action of MMPs, such as collagenase.18-21 Specifically, doxycycline (doxy) is considered to be the most potent tetracycline MMP inhibitor, whose activity is mediated both by direct and indirect mechanisms of action, and has been applied therapeutically in a variety of clinical applications.18-21 The use of doxy in tendon repair had been previously explored in vivo, though contradictory findings regarding its efficacy have been reported. [22][23][24] Consequently, MMP inhibitors and their activity ...

Assessing the effects of intratendinous genipin injections: Mechanical augmentation and spatial distribution in an ex vivo degenerative tendon model

“…[12][13][14] Even though some options offer good short-term improvements, long-term benefits are limited and results are inconclusive. [15][16][17][18][19][20][21] Strengthening exercises improve symptoms and muscle-tendon function, but may in turn increase the risk for further mechanical damage. [22] Whereas most of these therapies aim to improve the healing capacity of the tissue, an alternative approach is to augment the mechanical strength of the affected tendon in order to prevent further damage accumulation.…”

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