Mechanical Loading and TGF-β Regulate Proteoglycan Synthesis in Tendon

Robbins, J B; Evanko, Stephen P.; Vogel, Kathryn G.

doi:10.1006/abbi.1997.0102

Cited by 182 publications

(133 citation statements)

References 32 publications

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“…Interestingly, we were unable to detect a significant difference in proteoglycan synthesis rates between cells mechanically stretched for 48 hours as compared to their non-stretched controls. However, since proteoglycan synthesis rates were measured in the present study as the rate of 35 SO 4 incorporation into CPC-precipitable glycosaminoglycans, we can not exclude the possibility that in response to equibiaxial stretch, scleral fibroblasts alter their profile of proteoglycan gene expression, as has been demonstrated for that of fetal bovine deep flexor tendon during cyclic compression (Evanko and Vogel, 1993;Robbins et al, 1997) where synthesis of aggrecan is increased after 72 hours of cyclic compression, but decorin synthesis remains unchanged. In the present study, although the net amount of 35 SO 4 into newly synthesized glycosaminoglycans is unchanged, the population of proteoglycans may be similarly modified to produce a more compliant extracellular matrix.…”

Section: Effect Of Equibiaxial Stretch On the Rate Of Proteoglycan Symentioning

confidence: 77%

Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Shelton

Rada

2007

Experimental Eye Research

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In order to understand the effect of mechanical strain on scleral extracellular matrix remodeling, human scleral fibroblasts were subjected to equibiaxial stretch in vitro and the expression of proteoglycans, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were evaluated.Isolated human scleral fibroblasts were seeded onto flexible bottom culture plates, and subjected to a cyclic stretch regimen of 15% equibiaxial stretch for 45 seconds followed by 15 seconds of rest for 6 -48 hours in the presence of 35 SO 4 . Newly synthesized proteoglycans were measured in the medium by CPC precipitation of radiolabelled glycosaminoglycans. MMP-2 activity and expression levels were measured in the medium by, Western blot, gel zymography and real-time PCR. Steady state levels of TIMP-2 mRNA and membrane-type MMP, MT1-MMP (MMP-14) mRNA were measured in the cell layer using real-time PCR.The predominant gelatinolytic enzyme secreted by scleral fibroblasts was the pro-enzyme form of MMP-2 (ProMMP-2). Mechanical stretch resulted in a significant increase of ProMMP-2 after 12 and 48 hours (+76.28%, p < 0.05; +19.56%, p < 0.01, respectively). Mechanical stretch significantly increased the production of the active form of MMP-2 (ActiveMMP-2) after 48 hours (+59.72%, p < 0.05) and decreased levels of TIMP-2 mRNA (−22%, p < 0.05). The rate of scleral proteoglycan synthesis and the steady state levels of MMP-2 and MMP-14 mRNA were not significantly affected by mechanical stretch.These results suggest that mechanical strain stimulates the activation of MMP-2 by scleral fibroblasts, possibly through increased levels of ProMMP-2 and reduced levels of TIMP-2. Increased levels of ActiveMMP-2 in the sclera would be expected to contribute to scleral extracellular matrix degradation, scleral thinning and possible ocular ectasia.

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Section: Effect Of Equibiaxial Stretch On the Rate Of Proteoglycan Symentioning

confidence: 77%

Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Shelton

Rada

2007

Experimental Eye Research

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“…Taken together, our results, coupled with published studies reporting similarly observed changes in decorin and collagen type III protein distribution and mRNA levels, support the hypothesis that decorin and collagen type III are involved in collagen fibrillogenesis. Although TGF-␤s have been shown to induce production of collagen type III (Balza et al, 1988;Saed et al, 1999;Klein et al, 2002), decorin production is not affected (Robbins et al, 1997). However, binding of TGF-␤ by decorin and fibronectin has been reported (Mooradian et al, 1989;Yamaguchi et al, 1990;Schonherr et al, 1998), and blocking decorin gene expression results in suppression of TGF-␤1 production (Hosaka et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, in vivo treatment of injured ligament by antisense decorin oligodeoxynucleotides resulted in larger collagen fibrils and a significant improvement in mechanical properties, compared with control treatments (Nakamura et al, 2000). In vitro, TGF-␤1 has been reported to stimulate mitogenic responses of cultured patellar tendon fibroblasts (Spindler et al, 1996) and mediate proteoglycan synthesis in tendon explants (Robbins et al, 1997). While these studies have served as the basis for developing strategies to improve adult tendon and ligament healing using TGF-␤s, the approaches are largely focused on enhancing mechanical properties of scar tissue rather than regenerating normal, scarless tissue.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

Kuo

Petersen

Tuan

2008

Developmental Dynamics

109

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Tendon is one of the least understood tissues of the musculoskeletal system in terms of development and morphogenesis. Collagen fibrillogenesis has been the most studied aspect of tendon development, focusing largely on the role of matrix molecules such as collagen type III and decorin. While involvement of matrix molecules in collagen fibrillogenesis during chick tendon development is well understood, the role of growth factors has yet to be elucidated. This work examines the expression patterns of transforming growth factor (TGF) -␤1, -␤2, and -␤3, and their receptors with respect to expression patterns of collagen type III, decorin, and fibronectin. We focus on the intermediate stages of tendon development in the chick embryo, a period during which the tendon micro-and macro-architecture are being established. Our findings demonstrate for the first time that TGF-␤1, -␤2, and -␤3 have distinct spatiotemporal developmental protein localization patterns in the developing tendon and strongly suggest that these isoforms have independent roles in tendon development.

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“…Versican has been reported to be upregulated by TGF-b in a variety of cells (Kahari et al, 1991;Schonherr et al, 1991;Robbins et al, 1997;Venkatesan et al, 2002;Zhao and Russell, 2005). We have previously found that TGF-b2-specific phosphorothioate antisense molecules inhibit glioma migration in migration assays and downregulate versican expression in gene arrays (NicklJockschat et al, 2007).…”

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confidence: 99%

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

et al. 2007

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Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-b2 (TGF-b2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-b2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-b2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-b2 and inhibited by TGF-b2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-b domain of versican was able to reverse the effect of TGF-b2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-b2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1.

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Mechanical Loading and TGF-β Regulate Proteoglycan Synthesis in Tendon

Cited by 182 publications

References 32 publications

Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

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