Inhibition of cartilage proteoglycan release by a specific inactivator of cathepsin b and an inhibitor of matrix metalloproteinases. evidence for two converging pathways of chondrocyte‐mediated proteoglycan degradation

Buttle, David J.; Handley, Christopher J.; Ilic, Mirna Z.; Saklatvala, Jeremy; Murata, Mitsuo; Barrett, Alan J.

doi:10.1002/art.1780361210

Cited by 117 publications

(76 citation statements)

References 35 publications

(47 reference statements)

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“…This was evidenced by increase in the level of matrix components like fibronectin in synovial effusate and synovial fluid (SF) and membrane receptors for matrix proteins like integrins in soluble form in synovial fluid (data not shown). Although there are reports on the matrix degradation due to alteration in the activities of MMPs in osteoarthritis (28)(29)(30)(31), our results indicates that there occurs a sequential change in the level of different MMPs. Our results on the differential appearance of MMPs in synovial effusate during the progression of the disease in experimental animals particularly the appearance of MMP-3 during the initial stages provide further insight into the molecular mechanisms involved in the degradation of cartilage during arthritis and suggest that probably MMP-3, is a key enzyme involved in the initiation of this event.…”

Section: Discussioncontrasting

confidence: 70%

Multiple matrix metalloproteinases in type II collagen induced arthritis

Sandya

Achan²,

Sudhakaran

2009

Indian J Clin Biochem

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Section: Discussioncontrasting

confidence: 70%

Multiple matrix metalloproteinases in type II collagen induced arthritis

Sandya

Achan²,

Sudhakaran

2009

Indian J Clin Biochem

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“…Figure 7 summarizes known activation cascades that lead to generation of active collagenases and shows where furin and plasmin may be involved. The activation cascades in vivo are likely to be more complex, possibly involving other enzymes such as cysteine proteinases (52).…”

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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“…Second, retinoic acid and pro-inflammatory cytokines (IL-1 and TNF-α) are known to upregulate the expression of several MMPs, and this promotes aggrecan loss from cartilage explants [41][42][43]. This loss of aggrecan can be prevented by adding specific inhibitors of MMPs to the conditioned medium [44], [45]. Third, the N-and C-terminal neoepitopes generated by MMPs are present in both cartilage and synovial fluid.…”

Section: The Inter-globular Domain (Igd)mentioning

confidence: 99%

Structure and function of aggrecan

et al. 2002

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Aggrecan is the major proteoglycan in the articular cartilage. This molecule is important in the proper functioning of articular cartilage because it provides a hydrated gel structure (via its interaction with hyaluronan and link protein) that endows the cartilage with load-bearing properties. It is also crucial in chondroskeletal morphogenesis during development. Aggrecan is a multimodular molecule expressed by chondrocytes. Its core protein is composed of three globular domains (G1, G2, and G3) and a large extended region (CS) between G2 and G3 for glycosaminoglycan chain attachment. G1 comprises the amino terminus of the core protein. This domain has the same structural motif as link protein. Functionally, the G1 domain interacts with hyaluronan acid and link protein, forming stable ternary complexes in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and of link protein and is involved in product processing. G3 makes up the carboxyl terminus of the core protein. It enhances glycosaminoglycan modification and product secretion. Aggrecan plays an important role in mediating chondrocyte-chondrocyte and chondrocyte-matrix interactions through its ability to bind hyaluronan.

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Inhibition of cartilage proteoglycan release by a specific inactivator of cathepsin b and an inhibitor of matrix metalloproteinases. evidence for two converging pathways of chondrocyte‐mediated proteoglycan degradation

Cited by 117 publications

References 35 publications

Multiple matrix metalloproteinases in type II collagen induced arthritis

Multiple matrix metalloproteinases in type II collagen induced arthritis

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

Structure and function of aggrecan

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