Matrix metalloproteases: a role in overuse tendinopathies

Magra, Merzesh; Maffulli, Nicola

doi:10.1136/bjsm.2005.017855

Cited by 117 publications

(112 citation statements)

References 20 publications

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“…The activities of MMPs are inhibited by a family of tissue inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). This family contains four human gene products, namely TIMP1, TIMP2, TIMP3, and TIMP4 [71]. All TIMP members inhibit MMP members to varying degrees [13], however, only TIMP-3 is a potent inhibitor of members of ADAM and ADAMTS [5,45,56].…”

Section: Metalloproteinases and Their Inhibitorsmentioning

confidence: 99%

The Basic Science of Tendinopathy

Murrell

2008

Clinical Orthopaedics &Amp; Related Research

314

254

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Tendinopathy is a common clinical problem with athletes and in many occupational settings. Tendinopathy can occur in any tendon, often near its insertion or enthesis where there is an area of stress concentration, and is directly related to the volume of repetitive load to which the tendon is exposed. Recent studies indicate tendinopathy is more likely to occur in situations that increase the ''dose'' of load to the tendon enthesis -including increased activity, weight, advancing age, and genetic factors. The cells in tendinopathic tendon are rounder, more numerous, and show evidence of oxidative damage and more apoptosis. These cells also produce a matrix that is thicker and weaker with more water, more immature and cartilage-like matrix proteins, and less organization. There is now evidence of a population of regenerating stem cells within tendon. These studies suggest prevention of tendinopathy should be directed at reducing the volume of repetitive loads to below that which induces oxidative-induced apoptosis and cartilage-like genes. The management strategies might involve agents or cells that induce tendon stem cell proliferation, repair and restoration of matrix integrity.

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Section: Metalloproteinases and Their Inhibitorsmentioning

confidence: 99%

The Basic Science of Tendinopathy

Murrell

2008

Clinical Orthopaedics &Amp; Related Research

314

254

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“…Indeed, in vitro experimental studies have demonstrated that loss of homeostatic tendon strain can produce a pattern of catabolic gene expression [5,[33][34][35][36]41], apoptosis [3,17], and degenerative histological changes [5,21] similar to those seen in clinical cases of tendinopathy [1,2,5,19,24,26,28,30,31,38,39,40,45,50,54,60,61]. However, the effect of these catabolic changes on the subsequent mechanoresponsiveness of tendon cells is unknown.…”

Section: Introductionmentioning

confidence: 99%

Loss of Homeostatic Strain Alters Mechanostat “Set Point” of Tendon Cells In Vitro

Arnoczky

Lavagnino

Egerbacher

et al. 2008

Clinical Orthopaedics &Amp; Related Research

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Tendon cells respond to mechanical loads. The character (anabolic or catabolic) and sensitivity of this response is determined by the mechanostat set point of the cell, which is governed by the cytoskeleton and its interaction with the extracellular matrix. To determine if loss of cytoskeletal tension following stress deprivation decreases the mechanoresponsiveness of tendon cells, we cultured rat tail tendons under stress-deprived conditions for 48 hours and then cyclically loaded them for 24 hours at 1%, 3%, or 6% strain at 0.17 Hz. Stress deprivation upregulated MMP-13 mRNA expression and caused progressive loss of cellmatrix contact compared to fresh controls. The application of 1% strain to fresh tendons for 24 hours inhibited MMP-13 mRNA expression compared to stress-deprived tendons over the same period. However, when tendons were stressdeprived for 48 hours and then subjected to the same loading regime, the inhibition of MMP-13 mRNA expression was decreased. In stress-deprived tendons, it was necessary to increase the strain magnitude to 3% to achieve the same level of MMP-13 mRNA inhibition seen in fresh tendons exercised at 1% strain. The data suggest loss of cytoskeletal tension alters the mechanostat set point and decreases the mechanoresponsiveness of tendon cells.

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“…[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.…”

mentioning

confidence: 99%

“…[7][8][9][10][11][12][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.…”

mentioning

confidence: 99%

Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline

Kessler

Barr

Greenwald

et al. 2013

Journal Orthopaedic Research

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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 ...

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Matrix metalloproteases: a role in overuse tendinopathies

Cited by 117 publications

References 20 publications

The Basic Science of Tendinopathy

The Basic Science of Tendinopathy

Loss of Homeostatic Strain Alters Mechanostat “Set Point” of Tendon Cells In Vitro

Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline

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