Relationship of matrix metalloproteinases and their inhibitors to cartilage proteoglycan and collagen turnover: Analyses of synovial fluid from patients with osteoarthritis

Ishiguro, Naoki; Ito, Tetsuhide; H, Ito; Iwata, Hiroji; Jugessur, Hitu; Ionescu, Mirela; Ar, Poole

doi:10.1002/1529-0131(199901)42:1<129::aid-anr16>3.0.co;2-4

Cited by 100 publications

(75 citation statements)

References 37 publications

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“…ELISA demonstrated that the mean total TIMP-1 value, expressed as O.D. was 0.617 Ϯ 0.15 in synovial fluid harvested from groups I and II and 0.849 Ϯ 0.218 in fluid from groups III and IV (p Ͻ 0.02), thus indicating, on the whole, a slight increase of the total amount of TIMP-1 could be related to disease progression, as previously demonstrated [30]. However, synovial fluid Western blot analysis, performed under native conditions, has shown that very little TIMP-1 was bound to MMPs while more than 95% of the molecule was observed as a single band weighting about 20 kDa (data not shown).…”

Section: Identification Of Proteinase Inhibitors (Timp-1/2)supporting

confidence: 74%

“…In this respect, it is very important to outline that, even although the total amount of TIMP-2 (as confirmed in ref. [41]) and MMP-2 were similar among different groups, the extent of binding of TIMP-2 to MMP-2 (as from Western blot data obtained under native conditions by using anti TIMP-2 antibodies) turns out to be much less in patients of group IV with respect to patients from other groups (see Figure 7). This finding, which is very clearcut and might be used as a marker of the disease severity, could account for the increased MMP activity observed in the synovial fluids of these patients, allowing to propose MMP-2 as the most likely responsible for this phenomenon.…”

Section: Discussionmentioning

confidence: 71%

“…It must be remarked that the finding of different MMP activity patterns (as shown by zymography) despite a close similarity for the overall amount of active MMPs present in different synovial fluids (as shown by Western blot experiments performed by using anti-MMPs antibodies, see Figures 2-7) [41] suggests that the severity of the disease must be associated to the production of a MMP with either enhanced activity or reduced inhibition or with both. In this respect, it is very important to outline that, even although the total amount of TIMP-2 (as confirmed in ref.…”

Section: Discussionmentioning

confidence: 98%

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A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities

Marini

Fasciglione

Monteleone

et al. 2003

Clinical Biochemistry

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Objective: A novel study has been carried out to characterize the amount and activity levels of metalloproteinases (i.e., MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13) and of their inhibitors (i.e., TIMP-1 and TIMP-2) in synovial fluid from patients (n ϭ 56) with different degrees of either chondral lesions or knee arthritis identified and classified by arthroscopy. Design and methods: Zymographies, Western blotting and ELISA tests have been used to correlate the disease stage, as determined by arthroscopy, and both the amount and the activation state of different MMPs and of their inhibitors. Results: Analysis of data obtained demonstrates that the degree of cartilage degradation, as seen by arthroscopy, is strictly related to the activity of some synovial MMPs, in particular MMP-2 and MMP-13 and on reduced inhibitory effect of MMP-2 by TIMP-2; in addition, a serine protease weighing about 125 kDa appears only in patients with severe cartilage degradation, i.e., with knee arthritis. Conclusions: On the whole, this is the first study in which an analysis of synovial MMPs/other proteinases activity and TIMPs has been strictly related to arthroscopy results in patients with different degrees of osteoarthritis. Results indicate that an imbalance between specific MMP activities and the amount of TIMPs and of its inhibitory efficiency is crucial for the disease evolution and it is related to the disease stage.

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Section: Identification Of Proteinase Inhibitors (Timp-1/2)supporting

confidence: 74%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 98%

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A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities

Marini

Fasciglione

Monteleone

et al. 2003

Clinical Biochemistry

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“…These data suggest that MMP-3 does not represent the driving force in final matrix degradation in OA cartilage, which is further documented by the fact that MMP-3 knockout mice and their wild-type littermates are equally susceptible to cartilage destruction (51). Rather, MMP-3 appears to be a major contributor to physiologic matrix turnover in normal articular cartilage (52,53). Whereas the cDNA-array data showed no expression of MMP-1 and MMP-13 in normal cartilage, very low levels were detectable by TaqMan analysis.…”

Section: Discussionmentioning

confidence: 96%

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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“…Among the TIMPs identified in human chondrocytes, TIMP-2 has been reported to be constitutively expressed and therefore suggested to have a role in the maintenance of cartilage integrity in normal conditions, while TIMP-1 and TIMP-3 seem to have a more important role in pathological conditions [Zafarullah et al, 1996;Su et al, 1999]. High ratios of proteinase/inhibitors favor proteolysis and have been found in the synovial fluid of OA patients [Ishiguro et al, 1999].Members of the MMP and TIMP families are inversely regulated at the transcriptional level by catabolic stimuli, such as the proinflammatory cytokines, Interleukin-1b (IL-1) and Tumor Necrosis Factor-a (TNF), and by anabolic growth factors, namely Transforming Growth Factor-b (TGF). The last is especially important since it can act in articular chondrocytes in an autocrine and/or paracrine way, inducing anabolic effects and inhibiting catabolic responses.…”

mentioning

confidence: 99%

Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes

et al. 2011

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Cartilage matrix homeostasis involves a dynamic balance between numerous signals that modulate chondrocyte functions. This study aimed at elucidating the role of the extracellular glucose concentration in modulating anabolic and catabolic gene expression in normal and osteoarthritic (OA) human chondrocytes and its ability to modify the gene expression responses induced by pro-anabolic stimuli, namely Transforming Growth Factor-b (TGF). For this, we analyzed by real time RT-PCR the expression of articular cartilage matrix-specific and nonspecific genes, namely collagen types II and I, respectively. The expression of the matrix metalloproteinases (MMPs)-1 and -13, which plays a major role in cartilage degradation in arthritic conditions, and of their tissue inhibitors (TIMP) was also measured. The results showed that exposure to high glucose (30 mM) increased the mRNA levels of both MMPs in OA chondrocytes, whereas in normal ones only MMP-1 increased. Collagen II mRNA was similarly increased in normal and OA chondrocytes, but the increase lasted longer in the later. Exposure to high glucose for 24 h prevented TGF-induced downregulation of MMP-13 gene expression in normal and OA chondrocytes, while the inhibitory effect of TGF on MMP-1 expression was only partially reduced. Other responses were not significantly modified. In conclusion, exposure of human chondrocytes to high glucose, as occurs in vivo in diabetes mellitus patients and in vitro for the production of engineered cartilage, favors the chondrocyte catabolic program. This may promote articular cartilage degradation, facilitating OA development and/or progression, as well as compromise the quality and consequent in vivo efficacy of tissue engineered cartilage. J. Cell. Biochem. 112: 2813Biochem. 112: -2824Biochem. 112: , 2011. ß 2011 Wiley-Liss, Inc. KEY WORDS: COLLAGEN; GENE EXPRESSION; GLUCOSE; HUMAN CHONDROCYTE; MMP; OSTEOARTHRITIS; TIMPA rticular cartilage is a specialized connective tissue that supports and distributes loads and ensures a near-frictionless motion in joints. These unique properties are due to the structural organization of the main macromolecules that compose the cartilage extracellular matrix, namely collagens and proteoglycans. Chondrocytes, the only cell type present in articular cartilage, are embedded in the extracellular matrix and are responsible for maintaining its homeostasis by ensuring the synthesis and turnover of its components [Martel-Pelletier et al., 2008;Goldring and Marcu, 2009].Cartilage matrix homeostasis involves a dynamic balance between a variety of signals that modulate chondrocyte functions, namely mechanical forces, cytokines and growth factors and cellmatrix interactions, some favoring an anabolic program and others stimulating catabolic responses. Aging and mechanical stress of joints are major risk factors for osteoarthritis (OA), but growing evidence indicates that metabolic factors play an important role in disease development and progression. For instance, a significant positive correlation wa...

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Relationship of matrix metalloproteinases and their inhibitors to cartilage proteoglycan and collagen turnover: Analyses of synovial fluid from patients with osteoarthritis

Cited by 100 publications

References 37 publications

A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities

A correlation between knee cartilage degradation observed by arthroscopy and synovial proteinases activities

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

Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes

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