Preferential mRNA expression of prostromelysin relative to procollagenase and in situ localization in human articular cartilage.

Nguyen, Quang; Mort, John S.; Roughley, Peter J.

doi:10.1172/jci115702

Cited by 88 publications

(62 citation statements)

References 35 publications

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“…Despite many reports in the literature on the levels of expression of various collagenases and aggrecanases, no systematic comparative analysis of levels of expression of these enzymes is currently available, particularly in a representative series of in vivo cartilage samples. Most data relate to in situ hybridization analysis (3,29) or to in vitro studies based on a small number of cases (23). However, in situ hybridization is not quantitative and is prone to nonspecific reactions, and isolated chondrocytes show a largely altered pattern of expression, as was also documented by this study.…”

Section: Discussionsupporting

confidence: 64%

“…Strong expression of MMP-3 was suggested in some previous studies (2,3), whereas other studies could not confirm this (29). Of note, MMP-3 was significantly down-regulated in late-stage OA cartilage, which is consistent with the observation that chondrocytes isolated from OA cartilage express less MMP-3 than those isolated from normal articular cartilage (3), although other authors reported contradictory results (29,30).…”

Section: Discussionmentioning

confidence: 75%

“…Expression of a third candidate, collagenase 2 (MMP-8 or neutrophil collagenase), was not observed in previous experiments (2) and was, therefore, not investigated in this study. Expression of both MMP-1 and MMP-13 in articular cartilage has been reported (3)(4)(5).…”

mentioning

confidence: 99%

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Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Bau¹,

Gebhard²,

Haag³

et al. 2002

Arthritis & Rheumatism

370

322

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Objective. Osteoarthritic (OA) cartilage destruction depends on collagen-and aggrecan-degrading proteases such as collagenases (MMP-1 and MMP-13), stromelysin (MMP-3), MMP-14, as well as the so-called aggrecanases (ADAM-TS4 and ADAM-TS5). In this study, we tried to clarify whether these proteases are expressed in vivo in human normal and OA cartilage (and whether they are up-regulated or down-regulated during the disease process) and in interleukin-1␤ (IL-1␤)-stimulated chondrocytes in vitro.Methods. Quantitative polymerase chain reaction assays were developed and performed on RNA isolated directly from normal and degenerative cartilage tissue as well as from primary human articular chondrocytes cultured with and without IL-1␤.Results. In vivo, MMP-1 was detectable only at very low levels in any condition. MMP-13 expression was low in normal and early degenerative cartilage but was strongly up-regulated in late-stage OA specimens. MMP-1 and MMP-13 were expressed much higher in vitro than in vivo and were up-regulated by IL-1␤. Among all proteases, MMP-3 was by far the most strongly expressed, although it was strongly downregulated in late-stage OA specimens. Expression of MMP-3 was higher in vitro than in vivo and was up-regulated by IL-1␤. ADAM-TS5 and MMP-14 were expressed in all sample groups. Expression of ADAM-TS4 was very low in vivo and was induced in vitro after stimulation by IL-1␤.Conclusion. Our expression data clearly support MMP-13 as the major collagenase in OA cartilage. The most strongly expressed aggrecanase was ADAM-TS5. ADAM-TS4 was expressed only at a very low level in normal cartilage and was only slightly up-regulated in OA cartilage, casting doubt on this enzyme being the relevant aggrecanase of articular cartilage. Results of our study show that expression of many enzymes is significantly different in vitro and in vivo and suggest that IL-1␤ stimulation of articular chondrocytes might not be a good model for the matrix catabolism in OA cartilage.Osteoarthritic (OA) cartilage degeneration as well as cartilage destruction in rheumatoid arthritis depend, at least to a significant degree, on enzymatic degradation of matrix components. Two types of molecules, collagen fibrils and the proteoglycan aggrecan, represent the major targets in terms of enzymatic activity and functional loss of the cartilage matrix as a result of damage to these molecules. Whereas degradation of collagen fibrils leads to matrix instability with tissue swelling, degradation of proteoglycans leads to cartilage softening and loss of fixed charges (1), both of which are classic features of cartilage destruction.Catabolism of both types of molecules is supposed to involve different types of enzymes, largely from 2 protease families: matrix metalloproteinases (MMPs) and the "A disintegrin and metalloproteinases with thrombospondin type 1 motif" (ADAM-TS). The initial degradation of collagen fibrils (within the triple-helical region) depends on cleavage at the collagenase site, for which there exist 2 major candidate enzymes...

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 75%

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Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Bau¹,

Gebhard²,

Haag³

et al. 2002

Arthritis & Rheumatism

370

322

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“…The data for mRNA expression of MMP-3 are more contradictory. Using Northern blotting, Nguyen et al (54) found abundant expression of MMP-3 mRNA in "normal" cartilage and loss of message in late-stage OA cartilage. By in situ hybridization, the message in "normal" cartilage was localized to chondrocytes of the superficial zone, similar to our immunolocalization in low-grade OA.…”

Section: Discussionmentioning

confidence: 99%

Association between the abnormal expression of matrix‐degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions

Roach

Yamada

Cheung

et al. 2005

Arthritis & Rheumatism

319

275

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Objective. To investigate whether the abnormal expression of matrix metalloproteinases (MMPs) 3, 9, and 13 and ADAMTS-4 by human osteoarthritic (OA) chondrocytes is associated with epigenetic "unsilencing."Methods. Cartilage was obtained from the femoral heads of 16 patients with OA and 10 control patients with femoral neck fracture. Chondrocytes with abnormal enzyme expression were immunolocalized. DNA was extracted, and the methylation status of the promoter regions of MMPs 3, 9, and 13 and ADAMTS-4 was analyzed with methylation-sensitive restriction enzymes, followed by polymerase chain reaction amplification.Results. Very few chondrocytes from control cartilage expressed the degrading enzymes, whereas all clonal chondrocytes from late-stage OA cartilage were immunopositive. The overall percentage of nonmethylated sites was increased in OA patients (48.6%) compared with controls (20.1%): 20% versus 4% for MMP-13, 81% versus 47% for MMP-9, 57% versus 30% for MMP-3, and 48% versus 0% for ADAMTS-4. Not all CpG sites were equally susceptible to loss of methylation. Some sites were uniformly methylated, whereas in others, methylation was generally absent. For each enzyme, there was 1 specific CpG site where the demethylation in OA patients was significantly higher than that in controls: at -110 for MMP-13, -36 for MMP-9, -635 for MMP-3, and -753 for ADAMTS-4.Conclusion. This study provides the first evidence that altered synthesis of cartilage-degrading enzymes by late-stage OA chondrocytes may have resulted from epigenetic changes in the methylation status of CpG sites in the promoter regions of these enzymes. These changes, which are clonally transmitted to daughter cells, may contribute to the development of OA.Osteoarthritis (OA) is characterized by the progressive failure of the extracellular cartilage matrix, which leads to the destruction of articular cartilage (1,2). Primary OA is a late-onset complex disease with genetic, mechanical, and environmental components. Concordance of the disease in monozygotic twins is 40-60%, and the overall contribution of genetic factors is estimated to be ϳ50% (3). Given that more than 60% of unrelated adults over the age of 60 years are affected, other factors must also play a role in the development of this disease. Age, obesity, abnormal joint loading, and sports injuries are all risk factors, but OA is more than just the result of "wear and tear" (4,5). Articular chondrocytes are increasingly being suspected of playing major roles in the initiation and progression of the disease (1). This warrants closer examination of the cellular changes that occur in OA.The main extracellular matrix components of articular cartilage are collagens (principally, types II, IX, and XI) and proteoglycans (mainly, aggrecan). The major enzymes that mediate the destructive processes are aggrecanases 1 and 2 (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases (MMPs) 2 (gelatinase A),

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“…A major feature of cartilage degeneration associated with arthritis is loss of aggrecan due to proteolytic cleavage within the interglobular region between the G1 and G2 globular domains. The proteinase(s) responsible for aggrecan degradation in the tissue have not been identified, but much interest has focused on the role of the matrix metalloproteinases in arthritic disease [1][2][3][4][5][6][7][8][9][10]. A predominant MMP cleavage site in the aggrecan interglobular domain has been identified between N341 and F342.…”

Section: Introductionmentioning

confidence: 99%

Degradation of cartilage aggrecan by collagenase‐3 (MMP‐13)

Fosang

Knäuper²,

Murphy³

et al. 1996

FEBS Letters

345

217

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Preferential mRNA expression of prostromelysin relative to procollagenase and in situ localization in human articular cartilage.

Cited by 88 publications

References 35 publications

Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Association between the abnormal expression of matrix‐degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions

Degradation of cartilage aggrecan by collagenase‐3 (MMP‐13)

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