Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: Associations with degenerative changes

Tetlow, Lesley; Adlam, Daman J.; Woolley, David

doi:10.1002/1529-0131(200103)44:3<585::aid-anr107>3.3.co;2-3

Cited by 165 publications

(221 citation statements)

References 21 publications

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“…Recently, chondrocytes in the superficial and medial zone in OA cartilage have been reported to be positive for IL-1␤ and TNF-␣ compared with normal cartilage using immunohistologic methods (32). We have also shown functional up-regulation of TNF-␣ and TNF-␣ convertase activity in human OA-and RA-affected cartilage compared with normal (33).…”

Section: Discussionsupporting

confidence: 49%

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Attur

Dave

Leung

et al. 2002

The Journal of Immunology

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Gene expression arrays show that human epithelial cells and human arthritis-affected cartilage lack detectable amounts of mRNA for IL-1 antagonizing molecules: IL-1Ra and IL-1RII, but constitutively express IL-1. Functional genomic analysis was performed by reconstituting human IL-1RII expression in various IL-1RII-deficient cell types to examine its antagonist role using gene therapy approaches. Adenovirus-expressing IL-1RII when transduced into human and bovine chondrocytes, human and rabbit synovial cells, human epithelial cells, and rodent fibroblasts expressed membrane IL-1RII and spontaneously released functional soluble IL-1RII. The IL-1RII+ (but not IL-1RII−) cells were resistant to IL-1β-induced, NO, PGE2, IL-6, and IL-8 production or decreased proteoglycan synthesis. IL-1RII inhibited the function of IL-1 in chondrocytes and IL-1- and TNF-α-induced inflammatory mediators in human synovial and epithelial cells. IL-1RII+ chondrocytes were more resistant to induction of NO and PGE2 by IL-1β compared with IL-1RII− cells incubated with a 10-fold (weight) excess of soluble type II IL-1R (sIL-1RII) protein. In cocultures, IL-1RII+ synovial cells released sIL-1RII, which in a paracrine fashion protected chondrocytes from the effects of IL-1β. Furthermore, IL-1RII+ (but not IL-1RII−) chondrocytes when transplanted onto human osteoarthritis-affected cartilage in vitro, which showed spontaneous release of sIL-1RII for 20 days, inhibited the spontaneous production of NO and PGE2 in cartilage in ex vivo. In summary, reconstitution of IL-1RII in IL-1RII− cells using gene therapy approaches significantly protects cells against the autocrine and paracrine effects of IL-1 at the signaling and transcriptional levels.

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Section: Discussionsupporting

confidence: 49%

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Attur

Dave

Leung

et al. 2002

The Journal of Immunology

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“…Moreover, we recently demonstrated that the combination of IL-1␣ and OSM was able to synergistically induce messenger RNA (mRNA) expression for all 3 collagenases in chondrocytes, with a concomitant increase in MT1-MMP expression (66). Increased MMP-1 expression has also been detected in rheumatoid synovium and cartilage (67) and in osteoarthritic cartilage (68). MMP-13 protein is present in the pannus-hard tissue junction in RA (69) and in osteoarthritic cartilage (68).…”

Section: Discussionmentioning

confidence: 99%

“…Increased MMP-1 expression has also been detected in rheumatoid synovium and cartilage (67) and in osteoarthritic cartilage (68). MMP-13 protein is present in the pannus-hard tissue junction in RA (69) and in osteoarthritic cartilage (68). However, type II collagen is the principal collagen in cartilage and is cleaved most efficiently by MMP-13 (25,63).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

Milner¹,

Rowan²,

Sf³

et al. 2003

Arthritis & Rheumatism

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Objective. To investigate the role of furin-like enzymes in the proteolytic cascades leading to cartilage breakdown and to examine which collagenase(s) contribute to collagen degradation.Methods. Bovine nasal cartilage was stimulated to resorb with the addition of interleukin-1␣ (IL-1␣)/ oncostatin M (OSM) in the presence or absence of a furin inhibitor, Dec-RVKR-CH 2 Cl, or selective matrix metalloproteinase 1 (MMP-1) inhibitors. Collagen and proteoglycan levels were determined by assay of hydroxyproline and sulfated glycosaminoglycan, respectively. Collagenase and gelatinase activity were measured using 3 H-acetylated collagen and gelatin zymography, respectively.Results. The addition of Dec-RVKR-CH 2 Cl to stimulated cartilage reduced the release of collagen fragments and the levels of active collagenase and MMP-2, suggesting that furin-like enzymes are involved in the cascades leading to activation of procollagenases. At MMP inhibitor concentrations that selectively inhibit MMP-1, no inhibition of collagen release was observed, but increasing the concentration to the 50% inhibition concentration for MMP-13 resulted in a 50% blockage of collagen release. The addition of Dec-RVKR-CH 2 Cl to resorbing cartilage also partially blocked proteoglycan release, thus demonstrating a role for furin-activated enzymes in the pathways leading to proteoglycan degradation. Conclusion.Furin-like enzymes are involved in cascades leading to activation of procollagenases and degradation of collagen. MMP-13, which can be activated by furin-processed membrane-type 1 MMP-1, appears to be a major collagenase involved in collagen degradation induced by IL-1␣/OSM. Furin-like enzymes also appear to play a role in the pathways leading to proteoglycan degradation. These findings are of importance when considering proteinase inhibition as a target for therapeutic intervention in arthritic diseases.

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“…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).…”

mentioning

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

156

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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Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: Associations with degenerative changes

Cited by 165 publications

References 21 publications

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Functional Genomic Analysis of Type II IL-1β Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

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

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