Up-Regulation of Matrix Metalloproteinase Expression and Activation Following Cyclical Compressive Loading of Articular Cartilage in Vitro

Blain, Emma Jane; Gilbert, Sophie; Wardale, R. John; Capper, S. J.; Mason, Deborah Jane; Duance, Victor Colin

doi:10.1006/abbi.2001.2575

Cited by 78 publications

(53 citation statements)

References 27 publications

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“…Dynamic compression, a known stimulator of matrix protein synthesis, was also found to induce MMP-2 and -9 gene expression and activity (11). In our study, matrix protease gene expression followed a common trend of increasing up-regulation with 50% compression duration ( Fig.…”

Section: Discussionsupporting

confidence: 64%

“…Application of 50% static compression to cartilage explants decreased synthesis of type II collagen and proteoglycans (PG) within the first 1-2 h of loading, and synthesis remained suppressed throughout a 24-h loading period (6 -8). Dynamic compression (8,9) and shear (10) increased type II collagen and PG synthesis at low amplitudes and frequencies (1-5% strain, 0.01-1 Hz); however, compression also increased the activation of MMP-2 and MMP-9 (11). Injurious compression of cartilage explants results in increased PG loss to medium and damage to the collagen network (12,13).…”

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confidence: 99%

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Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP

Fitzgerald

Jin

Dean

et al. 2004

Journal of Biological Chemistry

221

184

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Chondrocytes are influenced by mechanical forces to remodel cartilage extracellular matrix. Previous studies have demonstrated the effects of mechanical forces on changes in biosynthesis and mRNA levels of particular extracellular matrix molecules, and have identified certain signaling pathways that may be involved. However, the broad extent and kinetics of mechano-regulation of gene transcription has not been studied in depth. We applied static compressive strains to bovine cartilage explants for periods between 1 and 24 h and measured the response of 28 genes using real time PCR. Compression time courses were also performed in the presence of an intracellular calcium chelator or an inhibitor of cyclic AMP-activated protein kinase A. Cluster analysis of the data revealed four main expression patterns: two groups containing either transiently up-regulated or duration-enhanced expression profiles could each be subdivided into genes that did or did not require intracellular calcium release and cyclic AMP-activated protein kinase A for their mechano-regulation. Transcription levels for aggrecan, type II collagen, and link protein were up-regulated ϳ2-3-fold during the first 8 h of 50% compression and subsequently down-regulated to levels below that of free-swelling controls by 24 h. Transcription levels of matrix metalloproteinases-3, -9, and -13, aggrecanase-1, and the matrix protease regulator cyclooxygenase-2 increased with the duration of 50% compression 2-16-fold by 24 h. Thus, transcription of proteins involved in matrix remodeling and catabolism dominated over anabolic matrix proteins as the duration of static compression increased. Immediate early genes c-fos and c-jun were dramatically up-regulated 6 -30-fold, respectively, during the first 8 h of 50% compression and remained up-regulated after 24 h. Articular cartilage is responsible for the smooth articulation of synovial joints during locomotion. Chondrocytes within cartilage constantly remodel the extracellular matrix (ECM) 1 of the tissue throughout life. The major load-bearing constituents of the ECM are type II collagen and aggregates of the proteoglycan, aggrecan, which provide the tensile and compressive stiffness of the tissue, respectively. Also present in the ECM are families of matrix proteinases, tissue inhibitors of matrix metalloproteinases (TIMPs), growth factors, and cytokines that together regulate ECM remodeling and turnover in health and disease (1). It is known that mechanical exercise of the knee joint in vivo increases the density of aggrecan in cartilage (2), whereas knee joint inactivity results in decreased aggrecan deposition (3, 4). Traumatic injury to cartilage diminishes mechanical strength and leads to excessive catabolism of the ECM, increasing the risk of osteoarthritis later in life (5).A number of model systems have been developed to simulate various aspects of the mechanical loading forces experienced by articular cartilage in vivo. Compressive and shear forces have been applied to cartilage explants and chondrocyte cul...

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Section: Discussionsupporting

confidence: 64%

mentioning

confidence: 99%

Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP

Fitzgerald

Jin

Dean

et al. 2004

Journal of Biological Chemistry

221

184

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“…[5][6][7][8][9]13,[15][16][17][18][19][20] Variations in the proteoglycan content of cartilage in different sites have been shown in both animal and human studies. 18,[21][22][23] These considered the absolute concentration of proteoglycan in cartilage without relating it to chondrocyte density.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 This involves cellular, molecular and genetic pathways leading to some form of altered gene expression. 15,16,18,19,22 The integrin family of dimeric transmembrane proteins are considered to be the principal vehicle of the cell/matrix interaction. 31 This triggers a plethora of intracellular pathways which alter gene expression, thus modifying both the biosynthesis and biodegradation of the ECM.…”

Section: Discussionmentioning

confidence: 99%

Topographical variation in glycosaminoglycan content in human articular cartilage

Rogers

Murphy

Cannon

et al. 2006

The Journal of Bone and Joint Surgery. British volume

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The weight-bearing status of articular cartilage has been shown to affect its biochemical composition. We have investigated the topographical variation of sulphated glycosaminoglycan (GAG) relative to the DNA content of the chondrocyte in human distal femoral articular cartilage.Paired specimens of distal femoral articular cartilage, from weight-bearing and nonweight-bearing regions, were obtained from 13 patients undergoing above-knee amputation. After papain enzyme digestion, spectrophotometric GAG and fluorometric DNA assays assessed the biochemical composition of the samples. The results were analysed using a paired t-test.Although there were no significant differences in cell density between the regions, the weight-bearing areas showed a significantly higher concentration of GAG relative to DNA when compared with non-weight-bearing areas (p = 0.02).We conclude that chondrocytes are sensitive to their mechanical environment, and that local loading conditions influence the metabolism of the cells and hence the biochemical structure of the tissue.

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“…Acute overloading of the explanted tissue then yields matrix damage and cell death significantly greater than nonpreloaded controls. A recent study by others shows a significant loss of tissue PG and cell death with production of matrix metalloproteinase (MMP-3) adjacent to damaged collagen fibers under cyclic compression at 0.5 Hz for intensities of 1 and 5 MPa over 24 h. 9 Similarly, under 0.5 MPa of 1 Hz cyclic loading, a significant increase in the MMP-2 and -9 synthesis was found after 3 h. 10 The combination of glucosamine-chondroitin sulfate (glcN-CS) was shown in in vitro studies to function as a ''biological response modifier'' that could boost the natural protective responses of tissue under adverse environmental conditions, such as mechanical compression. 11 Using human osteoarthritis (OA) articular cartilage, treatments with glcN sulfate increase aggrecan mRNA levels and decrease MMP-3 activity.…”

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confidence: 98%

High levels of glucosamine–chondroitin sulfate can alter the cyclic preload and acute overload responses of chondral explants

Wei

Haut

2009

Journal Orthopaedic Research

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A recent study by our laboratory showed that 14 days of low intensity, intermittent cyclic preloading of chondral explants elevated the concentration of proteoglycans (PGs) to cause a mechanical stiffening of the explants prior to an acute overload and limit the extent of tissue damage. Longer term loading to 21 days resulted in tissue degradation prior to the acute traumatic event and excessive damage from an acute overload. Previous studies by others showed that bathing chondral explants in a supplement of glucosaminechondroitin sulfate (glcN-CS) upregulated the synthesis of tissue PGs, particularly in stressed tissue, and the supplement served as an antiinflammatory agent. Our current hypothesis was that the supplementation of culture media with a high concentration of glcN-CS would upregulate the production of tissue PG and limit or mitigate long-term degradation of chondral explants under cyclic preloading and limit tissue damage in an acute overload. We showed that, in the presence of supplement, cyclic preloading significantly increased tissue PG content and matrix modulus by about 65 and 300%, respectively, at 21 days, resulting in a reduction of matrix damage and cell death following an acute overload. These data show a biological action of high concentrations of this supplement and its effect on the mechanical properties in this in vitro model. In vitro studies of impact loading 1,2 on cartilage show cell death and matrix damage. In contrast, in vitro and in vivo studies showed positive aspects of low intensity, intermittent compressive loading, such as increased biosynthesis of proteoglycans (PGs). [3][4][5] Changes in PG and collagen contents of cartilage significantly alter the mechanical properties of this tissue. 6 Thus, it is reasonable to assume that cyclic preloading of cartilage can alter its mechanical properties and help determine the extent of matrix damage and cell death that will occur due to the blunt force overloading of a joint, such as during an acute knee ligament rupture. 7 Recent studies in our laboratory show that low intensity, intermittent cyclic preloading of chondral explants prior to an acute overload yields an increase in the synthesis of tissue PGs, resulting in a less severe traumatic insult for an acute overload. 8 Between 14 and 21 days of cyclic preloading, the explants experience a significant PG loss that leads to a dramatic loss in mechanical properties. Acute overloading of the explanted tissue then yields matrix damage and cell death significantly greater than nonpreloaded controls. A recent study by others shows a significant loss of tissue PG and cell death with production of matrix metalloproteinase (MMP-3) adjacent to damaged collagen fibers under cyclic compression at 0.5 Hz for intensities of 1 and 5 MPa over 24 h. 9 Similarly, under 0.5 MPa of 1 Hz cyclic loading, a significant increase in the MMP-2 and -9 synthesis was found after 3 h. 10 The combination of glucosamine-chondroitin sulfate (glcN-CS) was shown in in vitro studies to function as a ''...

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Up-Regulation of Matrix Metalloproteinase Expression and Activation Following Cyclical Compressive Loading of Articular Cartilage in Vitro

Cited by 78 publications

References 27 publications

Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP

Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP

Topographical variation in glycosaminoglycan content in human articular cartilage

High levels of glucosamine–chondroitin sulfate can alter the cyclic preload and acute overload responses of chondral explants

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