Changes in matrix protein biochemistry and the expression of mRNA encoding matrix proteins and metalloproteinases in posterior tibialis tendinopathy

Corps, Anthony N.; Robinson, A. H. N.; Harrall, R L; Avery, Nicholas C.; Curry, Valerie; Hazleman, B. L.; Riley, Graham P.

doi:10.1136/annrheumdis-2011-200391

Cited by 36 publications

(37 citation statements)

References 46 publications

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“…The other histopathological changes observed in this study are similar to those reported in human tendinopathy [20, 27, 49–52], and previous experimental studies using surgical transection or repetitive exercise models [24, 39]. Our previous studies also found that these histopathological changes were distributed widely throughout the tendon after a focal injury [22].…”

Section: Discussionsupporting

confidence: 89%

Spatiotemporal variations in gene expression, histology and biomechanics in an ovine model of tendinopathy

et al. 2017

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Flexor tendinopathy is a common problem affecting humans and animals. Tendon healing is poorly understood and the outcomes of conservative and surgical management are often suboptimal. While often considered a localized injury, recent evidence indicates that in the short term, tendinopathic changes are distributed widely throughout the tendon, remote from the lesion itself. Whether these changes persist throughout healing is unknown. The aim of this study was to document gene expression, histopathological and biomechanical changes that occur throughout the superficial digital flexor tendon (SDFT) up to 16 weeks post-injury, using an ovine surgical model of tendinopathy. Partial tendon transection was associated with decreased gene expression for aggrecan, decorin, fibromodulin, tissue inhibitors of metalloproteinases (TIMPS 1, 2 and 3), collagen I and collagen II. Gene expression for collagen III, lumican and matrix metalloproteinase 13 (MMP13) increased locally around the lesion site. Expression of collagen III and MMP13 decreased with time, but compared to controls, collagen III, MMP13 and lumican expression remained regionally high throughout the study. An increase in TIMP3 was observed over time. Histologically, operated tendons had higher pathology scores than controls, especially around the injured region. A chondroid phenotype was observed with increased cellular rounding and marked proteoglycan accumulation which only partially improved with time. Biomechanically, partial tendon transection resulted in a localized decrease in elastic modulus (in compression) but only at 8 weeks postoperatively. This study improves our understanding of tendon healing, demonstrating an early ‘peak’ in pathology characterized by altered gene expression and notable histopathological changes. Many of these pathological changes become more localized to the region of injury during healing. Collagen III and MMP13 expression levels remained high close to the lesion throughout the study and may reflect the production of tendon tissue with suboptimal biomechanical properties. Further studies evaluating the long-term response of tendon to injury (6–12 months) are warranted to provide additional information on tendon healing and provide further understanding of the mechanisms underlying the pathology observed in this study.

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Section: Discussionsupporting

confidence: 89%

Spatiotemporal variations in gene expression, histology and biomechanics in an ovine model of tendinopathy

et al. 2017

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“…Since we found unchanged type I collagen expression, decreased MMP-2 expression, and a trend toward an increased MMP-3 expression (P ϭ 0.07), it seems clear that the gene expression profile of the rat Achilles tendons subjected to 12 wk of running does not fit well with that of a tendinopathic tendon. In further support of this, we found decreased levels of VEGF and proteoglycan mRNA (fibromodulin and biglycan), which are thought to be elevated with tendinopathy (4,12,13,36,38). These mRNA results serve to underline the more fundamental finding of unchanged tissue histology, which clearly indicates that the training model does not induce Achilles tendinopathy.…”

Section: Regulation Of Gene Expressionsupporting

confidence: 69%

“…There are, however, some common findings in studies that have investigated differences in mRNA expression in tendinopathic tendon tissue vs. healthy tissue. These include an increased expression of collagen I and III mRNA (12,14,26,27), increased levels of MMP-2 mRNA (3,12,26,27) and decreased levels of MMP-3 mRNA (12,14,26,27,28). Since we found unchanged type I collagen expression, decreased MMP-2 expression, and a trend toward an increased MMP-3 expression (P ϭ 0.07), it seems clear that the gene expression profile of the rat Achilles tendons subjected to 12 wk of running does not fit well with that of a tendinopathic tendon.…”

Section: Regulation Of Gene Expressionmentioning

confidence: 99%

Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes

Heinemeier

Skovgaard

Bayer

et al. 2012

Journal of Applied Physiology

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Little is known about the etiology of this disorder, and the development of a good animal model for overuse tendinopathy is essential for advancing insight into the disease mechanisms. Our aim was to test a previously proposed rat model for Achilles tendon overuse. Ten adult male Sprague-Dawley rats ran on a treadmill with 10°incline, 1 h/day, 5 days/wk (17-20 m/min) for 12 wk and were compared with 12 control rats. Histological, mechanical, and gene-expression changes were measured on the Achilles tendons after the intervention, and local tendon glucose-uptake was measured before and after the intervention with positron emission tomography. No differences were detected between runners and controls in tissue histology or in glucose uptake, indicating that tendon pathology was not induced. Greater tendon tissue modulus (P Ͻ 0.005) and failure stress/body weight (P Ͻ 0.02) in runners compared with controls further supported that tendons successfully adapted to uphill running. Several genes of interest were regulated after 12 wk of running. Expression of collagen III and insulin-like growth factor I was increased, while collagen I was unchanged, and decreases were seen in noncollagen matrix components (fibromodulin and biglycan), matrix degrading enzymes, transforming growth factor-␤1, and connective tissue growth factor. In conclusion, the tested model could not be validated as a model for Achilles tendinopathy, as the rats were able to adapt to 12 wk of uphill running without any signs of tendinopathy. Improved mechanical properties were observed, as well as changes in gene-expression that were distinctly different from what is seen in tendinopathy and in response to short-term tendon loading. loading; exercise; tendinopathy; collagen TENDONS TRANSMIT FORCE FROM muscle to bone during muscle contraction, and optimal, painless function of tendon tissue is essential in voluntary movement. Although tendons can withstand considerable force, repetitive movements can lead to overuse of tendon tissue, resulting in tendinopathy, which is characterized by pain during activity and significantly impaired performance (36). Tendinopathy is very common in relation to both sports and occupational loading (16,17,45), and, since treatment possibilities are still relatively poor, these conditions are often prolonged (36). Although the features of tendinopathy at the time point when symptoms occur are relatively well described, the etiology of overuse-related tendinopathy is still poorly understood. Thus we know that symptomatic human tendinopathy is characterized by histological changes, such as increased cell density, altered cell morphology, and disorganization of the collagen matrix (reviewed by Ref. 36). In addition, increased vascularization has been shown in tendinopathic tendon (8), and studies of gene expression commonly find higher levels of collagen I and III, proteoglycan, and matrix metalloproteinase (MMP)-2 mRNA, as well as decreased MMP-3 mRNA expression (3, 12-14, 26 -28). However, the events leading up to these chan...

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“…The current study did not include analysis of the proteoglycan degrading enzymes ADAMTS4 and ADAMTS5 to determine if the accumulation of sGAGs correlated with altered expression and/or activity of these enzymes. Increased proteoglycan deposition in tendon disease correlates with ADAMTS5 knockout [55] and with its reduced expression in human tendinopathy [56]. It is intriguing that in equine suspensory ligament desmitis, chondroprogenitor cells appear responsible for elevated aggrecan synthesis and its accumulation may arise due to the inactivation of ADAMSTS5 despite its increased expression [57].…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Naturally Occurring Tendinopathy

et al. 2013

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Tendon injuries are a common age-related degenerative condition where current treatment strategies fail to restore functionality and normal quality of life. This disease also occurs naturally in horses, with many similarities to human tendinopathy making it an ideal large animal model for human disease. Regenerative approaches are increasingly used to improve outcome involving mesenchymal stem cells (MSCs), supported by clinical data where injection of autologous bone marrow derived MSCs (BM-MSCs) suspended in marrow supernatant into injured tendons has halved the re-injury rate in racehorses. We hypothesized that stem cell therapy induces a matrix more closely resembling normal tendon than the fibrous scar tissue formed by natural repair. Twelve horses with career-ending naturally-occurring superficial digital flexor tendon injury were allocated randomly to treatment and control groups. 1X107 autologous BM-MSCs suspended in 2 ml of marrow supernatant were implanted into the damaged tendon of the treated group. The control group received the same volume of saline. Following a 6 month exercise programme horses were euthanized and tendons assessed for structural stiffness by non-destructive mechanical testing and for morphological and molecular composition.BM-MSC treated tendons exhibited statistically significant improvements in key parameters compared to saline-injected control tendons towards that of normal tendons and those in the contralateral limbs. Specifically, treated tendons had lower structural stiffness (p<0.05) although no significant difference in calculated modulus of elasticity, lower (improved) histological scoring of organisation (p<0.003) and crimp pattern (p<0.05), lower cellularity (p<0.007), DNA content (p<0.05), vascularity (p<0.03), water content (p<0.05), GAG content (p<0.05), and MMP-13 activity (p<0.02).Treatment with autologous MSCs in marrow supernatant therefore provides significant benefits compared to untreated tendon repair in enhancing normalisation of biomechanical, morphological, and compositional parameters. These data in natural disease, with no adverse findings, support the use of this treatment for human tendon injuries.

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Changes in matrix protein biochemistry and the expression of mRNA encoding matrix proteins and metalloproteinases in posterior tibialis tendinopathy

Cited by 36 publications

References 46 publications

Spatiotemporal variations in gene expression, histology and biomechanics in an ovine model of tendinopathy

Spatiotemporal variations in gene expression, histology and biomechanics in an ovine model of tendinopathy

Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes

Beneficial Effects of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Naturally Occurring Tendinopathy

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