Matrix Metalloproteinase Inhibitor CGS 27023A Protects COMP and Proteoglycan in the Bovine Articular Cartilage but not the Release of Their Fragments from Cartilage after Prolonged Stimulation <i>in Vitro</i> with IL‐1α

Ganu, Vishwas; Melton, Richard; Wang, Weigwang; D, Roberts

doi:10.1111/j.1749-6632.1999.tb07740.x

Cited by 6 publications

(5 citation statements)

References 5 publications

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“…In studies with isolated MMPs and substrates in solution, GM 6001 has increasing binding affinity for MMPs with decreasing pH (39), and in other tissue systems, may reduce production of inflammatory cytokines (including IL‐1α and IL‐1β, IL‐6, and tumor necrosis factor α) (40). CGS 27023A, however, has previously been used in cartilage explant cultures, at concentrations similar to those used in the present study (41, 42). In those studies, CGS had little effect on IL‐1α–stimulated GAG released to the culture medium, consistent with reports that IL‐1α induces aggrecanase, not MMP, activity (33, 43).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury

DiMicco

Patwari

Siparsky

et al. 2004

Arthritis & Rheumatism

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Objective. Acute joint injury leads to increased risk for osteoarthritis (OA). Although the mechanisms underlying this progression are unclear, early structural, metabolic, and compositional indicators of OA have been reproduced using in vitro models of cartilage injury. This study was undertaken to determine whether glycosaminoglycan (GAG) loss following in vitro cartilage injury is mediated by cellular biosynthesis, activation of enzymatic activity, or mechanical disruption of the cartilage extracellular matrix.Methods. Immature bovine cartilage was cultured for up to 10 days. After 3 days, groups of samples were subjected to injurious mechanical compression (single uniaxial unconfined compression to 50% thickness, strain rate 100% per second). GAG release to the medium was measured, and levels were compared with those in location-matched, uninjured controls. The effects of medium supplementation with inhibitors of biosynthesis (cycloheximide), of matrix metalloproteinase (MMP) activity (CGS 27023A or GM 6001), and of aggrecanase activity (SB 703704) on GAG release after injury were assessed.Results. GAG release from injured cartilage was highest during the first 4 hours after injury, but remained higher than that in controls during the first 24 hours postinjury, and was not affected by inhibitors of biosynthesis or degradative enzymes. GAG release during the period 24-72 hours postinjury was similar to that in uninjured controls, but the MMP inhibitor CGS 27023A reduced cumulative GAG loss from injured samples between 1 day and 7 days postinjury. Other inhibitors of enzymatic degradation or biosynthesis had no significant effect on GAG release.Conclusion. Injurious compression of articular cartilage induces an initially high rate of GAG release from the tissue, which could not be inhibited, consistent with mechanical damage. However, the finding that MMP inhibition reduced GAG loss in the days following injury suggests a potential therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury

DiMicco

Patwari

Siparsky

et al. 2004

Arthritis & Rheumatism

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“…Streptavidin-HRP was obtained from KPL (Gaithersburg, MD), and TMB substrate was purchased from Dako (Carpinteria, CA). The aggrecanase selective inhibitor, SB-703704, and the broad spectrum MMP inhibitor, CGS-27023A, were synthesized at GSK as described 6,31 . They were prepared as 10 mM stock solutions in 100% dimethyl sulfoxide (DMSO).…”

Section: Other Materialsmentioning

confidence: 99%

Development and characterization of a highly specific and sensitive sandwich ELISA for detection of aggrecanase-generated aggrecan fragments

Pratta

Leesnitzer

et al. 2006

Osteoarthritis and Cartilage

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“…However, it is not clear whether all broad-spectrum MMP inhibitors are active against MT-MMPs, which were not characterized until 1999, and may have some unique features in the structure of their catalytic domains 47 . It is therefore intriguing that CGS20723A, a broad-spectrum MMP inhibitor that potently inhibits the catalytic domain of MT4-MMP in solution 48 , does not appear to inhibit overall IL-1-induced GAG loss in tissue culture, but has been reported to protect against loss of pericellular GAG staining 49 . This could be explained if loss of pericellular GAG staining is due to p53 generated by MT4-MMP, whereas more generalized aggrecanolysis in the intercellular matrix is due to p68 and therefore confined to the C-terminal of aggrecan.…”

Section: Inhibition Of the Aggrecanolysis Pathwaymentioning

confidence: 99%

Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage

Patwari

Gao

Lee

et al. 2005

Osteoarthritis and Cartilage

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These studies support a central role for MT4-MMP in IL-1-induced cartilage aggrecanolysis and are consistent with the identification of p68 as the aggrecanase that cleaves within the CS2 domain, and of p53 as the aggrecanase that generates G1-NITEGE. Since the induction by IL-1 was not accompanied by marked changes in total ADAMTS4 protein, but rather in partial conversion of p68 to p53 and release of both from the tissue, we conclude that aggrecanolysis in this model system results from MT4-MMP-mediated processing of a resident pool of ADAMTS4 and release of the p68 and p53 from their normal association with the cell surface.

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Matrix Metalloproteinase Inhibitor CGS 27023A Protects COMP and Proteoglycan in the Bovine Articular Cartilage but not the Release of Their Fragments from Cartilage after Prolonged Stimulation in Vitro with IL‐1α

Cited by 6 publications

References 5 publications

Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury

Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury

Development and characterization of a highly specific and sensitive sandwich ELISA for detection of aggrecanase-generated aggrecan fragments

Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage

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