Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage.

Billinghurst, R. Clark; Dahlberg, Leif; Ionescu, Mirela; Reiner, A; Bourne, Roger; Rorabeck, Cecil H.; Mitchell, Peter G.; Hambor, John E.; Diekmann, Oliver; Tschesche, Harald; Chen, J; Wart, H Van; Poole, A. Robin

doi:10.1172/jci119316

Cited by 902 publications

(895 citation statements)

References 53 publications

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“…MMP‐3 was selected as it degrades other minor proteins in tendon matrix, including collagens III, IV, IX, and X, and also proteoglycans and elastin 28, 29, 30, 31, 32, 33. The C1,2C (or COL 2 3/4C short) antibody detects the carboxy terminus of fragmented type I and II collagen, cleaved by collagenases MMP‐1, MMP‐8 or MMP‐13 21, 34, 35, 36, 37…”

Section: Methodsmentioning

confidence: 99%

Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise

Spiesz

Thorpe

Chaudhry

et al. 2015

Journal Orthopaedic Research

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The role of inflammation in tendon injury is uncertain and a topic of current interest. In vitro studies of tendon accelerated overload damage can serve as a valuable source of information on the early stages of tendinopathy. Viable fascicle bundles from bovine flexor tendons were subjected to cyclic uniaxial loading from 1–10% strain. Immuno‐staining for inflammatory markers and matrix degradation markers was performed on the samples after mechanical testing. Loaded samples exhibited visible extracellular matrix damage, with disrupted collagen fibers and fiber kinks, and notable damage to the interfascicular matrix. Inflammatory markers COX‐2 and IL‐6 were only expressed in the cyclically loaded samples. Collagen degradation markers MMP‐1 and C1,2C were colocalized in many areas, with staining occurring in the interfascicular matrix or the fascicular tenocytes. These markers were present in control samples, but staining became increasingly intense with loading. Little MMP‐3 or MMP‐13 was evident in control sections. In loaded samples, some sections showed intense staining of these markers, again localized to interfascicular regions. This study suggests that inflammatory markers may be expressed rapidly after tendon overload exercise. Interestingly, both inflammation and damage‐induced matrix remodeling seem to be concentrated in, or in the vicinity of, the highly cellular interfascicular matrix. © 2015 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. J Orthop Res 33:889–897, 2015.

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Section: Methodsmentioning

confidence: 99%

Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise

Spiesz

Thorpe

Chaudhry

et al. 2015

Journal Orthopaedic Research

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“…Many cartilage explant studies have shown that aggrecanolysis preceeds collagenolysis (Billinghurst, et al, 1997;Kuroki, et al, 2005;Pratta, et al, 2003b;Zwerina, et al, 2004), and it has been suggested (Pratta, et al, 2003b) that aggrecan protects the collagen network from proteolytic attack.…”

Section: Introductionmentioning

confidence: 99%

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

et al. 2007

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Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase-or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors which were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP-and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the loss of dynamic compression and shear moduli was delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

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“…MMPs are considered to be important in the chondrolytic processes that contribute to the degenerative changes in OA cartilage (2)(3)(4). Recent studies have identified the messenger RNA (mRNA) for some MMPs, such as MMP-1, MMP-3, MMP-9, and MMP-13, in human OA cartilage (4,5), and other investigators have reported specific MMP proteins and collagenasemediated type II collagen degradation products (6,7). There is a consensus that these enzymes play a critical role in intrinsic chondrocyte-mediated degenerative changes of the cartilage matrix in OA.…”

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confidence: 99%

Inhibition of interleukin‐1β‐stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage

Julovi

Yasuda

Shimizu

et al. 2004

Arthritis & Rheumatism

153

122

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Objective. To investigate the mechanism of the inhibitory action of hyaluronan (HA) on interleukin-1␤ (IL-1␤)-stimulated production of matrix metalloproteinases (MMPs) in human articular cartilage.Methods. IL-1␤ was added to normal and osteoarthritic (OA) human articular cartilage in explant culture to stimulate MMP production. Articular cartilage was incubated or preincubated with a clinically used form of 800-kd HA to assess its effect on IL-1␤-induced MMPs. Levels of secreted MMPs 1, 3, and 13 in conditioned media were detected by immunoblotting; intracellular MMP synthesis in chondrocytes was evaluated by immunofluorescence microscopy. Penetration of HA into cartilage tissue and its binding to CD44 were analyzed by fluorescence microscopy using fluoresceinated HA. Blocking experiments with anti-CD44 antibody were performed to investigate the mechanism of action of HA.Results. Treatment and pretreatment with 800-kd HA at 1 mg/ml resulted in significant suppression of IL-1␤-stimulated production of MMPs 1, 3, and 13 in normal and OA cartilage explant culture. Fluorescence histocytochemistry revealed that HA penetrated cartilage tissue and localized in the pericellular matrix around chondrocytes. HA-binding blocking experiments using anti-CD44 antibody demonstrated that the association of HA with chondrocytes was mediated by CD44. Preincubation with anti-CD44 antibody, which suppressed IL-1␤-stimulated MMPs, reversed the inhibitory effect of HA on MMP production that was induced by IL-1␤ in normal and OA cartilage.Conclusion. This study demonstrates that HA effectively inhibits IL-1␤-stimulated production of MMP-1, MMP-3, and MMP-13, which supports the clinical use of HA in the treatment of OA. The action of HA on IL-1␤ may involve direct interaction between HA and CD44 on chondrocytes.Osteoarthritis (OA) is the most prevalent disease of articular joints and is the major cause of disability in the elderly. Pathophysiologic changes occur in OA cartilage due to the excessive expression of cartilagedegrading proteinases, the resultant progressive breakdown of collagen fibers, and the degradation of proteoglycan, mainly aggrecan (1).Matrix metalloproteinases (MMPs) are zinccontaining, calcium-dependent proteinases, which collectively degrade all components of the extracellular matrix. MMPs are considered to be important in the chondrolytic processes that contribute to the degenerative changes in OA cartilage (2-4). Recent studies have identified the messenger RNA (mRNA) for some MMPs, such as MMP-1, in human OA cartilage (4,5), and other investigators have reported specific MMP proteins and collagenasemediated type II collagen degradation products (6,7). There is a consensus that these enzymes play a critical role in intrinsic chondrocyte-mediated degenerative changes of the cartilage matrix in OA. Proinflammatory cytokines such as interleukin-1 (IL-1) strongly stimulate the expression of MMPs by chondrocytes in arthritis (8).Hyaluronan (HA) is a major component of synovial fluid and cartilage matrix, and it play...

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Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage.

Cited by 902 publications

References 53 publications

Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise

Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

Inhibition of interleukin‐1β‐stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage

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