Matrix Metalloproteinase and Tissue Inhibitor of Matrix Metalloproteinase mRNA Levels are Specifically Altered in Torn Rotator Cuff Tendons

Lo, Ian K.Y.; Marchuk, Linda L.; Hollinshead, Robert; Hart, David A.; Frank, Cyril B.

doi:10.1177/0363546503262200

Cited by 183 publications

(236 citation statements)

References 55 publications

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“…As observed with the painful samples, ruptured tendon samples possessed lower levels of MMP-3 mRNA compared with the normal tendon samples, which is consistent with previous results (7). However, unlike the painful tendons, in which the level of MMP-10 mRNA was also lower, the MMP-10 mRNA levels in the ruptured samples did not differ from those in the normal tendons, an observation consistent with recent findings in the torn rotator cuff (61).…”

Section: Discussionsupporting

confidence: 89%

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Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Jones¹,

Corps²,

Pennington³

et al. 2006

Arthritis & Rheumatism

261

284

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Objective. To profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons.Methods. Tendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real-time reverse transcription-polymerase chain reaction, normalized to 18S ribosomal RNA.Results. In comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P < 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP-3 and higher levels of ADAM-12 and MMP-23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP-1 in ruptured compared with normal tendons.Conclusion. The distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon.

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Section: Discussionsupporting

confidence: 89%

“…We also have shown that ruptured tendons have lower levels of TIMPs 2, 3, and 4 mRNA compared with normal tendons, and similar data were reported in the rotator cuff (61). Unlike the results in the rotator cuff study, however, an increase in the level of TIMP-1 mRNA was observed in the ruptured Achilles tendon samples.…”

Section: Discussionsupporting

confidence: 82%

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Jones¹,

Corps²,

Pennington³

et al. 2006

Arthritis & Rheumatism

261

284

View full text Add to dashboard Cite

show abstract

“…In contrast to the sheep tendons in the present study, no change in MMP-13 was seen in the torn human Achilles tendons (14), while in rotator cuff tears MMP-13 but not MMP-1 was significantly increased (43). Whether these represent true differences between tendons or different time-dependent cellular responses after initial mechanical insult (Ͻ48 hours in Achilles tendon and Ͼ6 months in rotator cuffs) is unclear.…”

Section: Discussioncontrasting

confidence: 81%

“…shown that a number of molecular changes occur within the diseased tendon, including altered content and expression of collagen and proteoglycan (PG) and expression of matrix-degrading enzymes (6)(7)(8)(9)(10)(11)(12)(13)(14). However, which if any of these changes precede and lead to rupture, and which are a consequence of tearing is unknown.…”

mentioning

confidence: 99%

Modulation of aggrecan and ADAMTS expression in ovine tendinopathy induced by altered strain

Smith

Sakurai

Smith

et al. 2008

Arthritis & Rheumatism

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Objective. To evaluate histologic, immunohistochemical, and molecular changes in tendon induced by altered strain in a large-animal model.Methods. A full-thickness partial-width laceration of the infraspinatus tendon was created in 5 sheep, while 5 sham-operated sheep were used as controls. Sheep were killed after 4 weeks, and 4 differentially stressed tendon regions (tensile or near bone attachment from overstressed or stress-deprived halves) were evaluated for histopathology, proteoglycan (PG) accumulation, and characterization of glycosaminoglycans and aggrecan catabolites. Gene expression of matrix components, enzymes, and inhibitors was analyzed by reverse transcriptase-polymerase chain reaction.Results. Histopathologic changes were detected in both overstressed and stress-deprived tensile tendon, but only in stress-deprived tendon near bone. In overstressed and stress-deprived tensile tendon, levels of keratan sulfate, chondroitin 4-sulfate, and chondroitin 6-sulfate were increased. In overstressed tensile tendon, levels of ADAMTS-generated aggrecan catabolites were increased. There was increased matrix metalloproteinase 13 (MMP-13) and decreased fibromodulin and decorin expression in all regions. Increased MMP-1, MMP-9, MMP-14, and ADAMTS-1 expression, and decreased type II collagen expression were restricted to stress-deprived tendon. In stress-deprived boneattachment regions, messenger RNA (mRNA) for aggrecan was decreased, and ADAMTS was increased. In overstressed tensile tendon, aggrecan mRNA was increased, and ADAMTS was decreased.Conclusion. The distinct molecular changes in adjacent tissue implicate altered strain rather than humoral factors in controlling abnormal tenocyte metabolism, and highlight the importance of regional sampling. Tendon abnormalities induced by increased strain are accompanied by increased aggrecan, decreased ADAMTS, and low PG expression, which may negatively impact the structural integrity of the tissue and predispose to rupture.Injuries of the shoulder due to overuse are increasingly prevalent in both the sporting arena and the workplace. Occupational injury of the shoulder is second only to neck and low back pain in the frequency of consultation by general practitioners, with the most common injury involving the rotator cuff. (1,2) The prevalence of rotator cuff conditions increases with age, from 30-50% in the seventh decade of life to a staggering 70-80% by the ninth (3,4). Although most cases are treated conservatively, many patients undergo surgical repair with a prolonged convalescence. There are no drugs to specifically treat disorders of the rotator cuff or other tendons, and many surgical repairs fail within 12 months (5). Lack of knowledge of the fundamental mechanisms that underlie tendon breakdown results in limited and inadequate management options for tendon disorders.

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“…They have been found to be at increased levels in several tendon pathologies and injury models. [43][44][45][46] Collagen IV and laminin are both substrates of MMP10. 47 Having found the optimal SNAP concentrations to maximize the increase in expression of a variety of extracellular matrix genes, we next sought to test the hypothesis that their upregulation resulted in an increase in cellular adhesion-a critical function of endogenous fibroblasts during all phases of wound healing, and one that is critically affected by ECM production.…”

Section: Discussionmentioning

confidence: 99%

Gene expression changes in SNAP-stimulated and iNOS-transfected tenocytes—expression of extracellular matrix genes and its implications for tendon-healing

Molloy¹,

Bock²,

Wang³

et al. 2006

J. Orthop. Res.

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Nitric oxide (NO) has a variety of physiological roles, including acting as a key mediator in various phases of tendon healing, but its importance as a modulator of gene expression during tendon healing has not been well studied. The current study used microarray analysis to elucidate global gene expression after transfection with inducible nitric oxide synthase (iNOS) in tenocytes isolated from the injured rotator cuff tendons of human patients. We show that the expression of a wide range of genes is affected by NO, with many activated genes having known roles in healing. Of particular significance is that NOS overexpression stimulates the transcription and translation of a range of extracellular matrix genes important to the structure of connective tissues such as tendons, including collagen Ia1, collagen IIIa1, collagen IVa5, biglycan, decorin, laminin, and matrix metalloproteinase 10 (MMP10). These genes were also shown to respond to stimulation by the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) in a dose-dependant manner. We further show that varying levels of NO significantly affect cellular adhesion in tenocytes, a critical process during tendon repair. These findings will be of use when optimizing the dose of NO delivery in further work investigating NO as potential treatment of tendon injuries. ß

show abstract

Matrix Metalloproteinase and Tissue Inhibitor of Matrix Metalloproteinase mRNA Levels are Specifically Altered in Torn Rotator Cuff Tendons

Abstract: With the known action of the matrix metalloproteinases and tissue inhibitors of metalloproteinase in extra-cellular matrix remodeling, these findings suggest that their roles in remodeling of rotator cuff tears should be further investigated.

Cited by 183 publications

References 55 publications

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Modulation of aggrecan and ADAMTS expression in ovine tendinopathy induced by altered strain

Gene expression changes in SNAP-stimulated and iNOS-transfected tenocytes—expression of extracellular matrix genes and its implications for tendon-healing

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