Purification and Cloning of Aggrecanase-1: A Member of the ADAMTS Family of Proteins

Tortorella, Micky D.; Burn, Timothy C.; Pratta, Michael A.; Abbaszade, Ilgar; Hollis, Jeannine M.; Liu, R.; Rosenfeld, Stuart A.; Copeland, Robert A.; Decicco, Carl P.; Wynn, Richard; Rockwell, A. L.; Yang, Fan; Duke, Jodie L.; Solomon, Kimberly A.; George, Henry J.; Brückner, R.; Nagase, Hideaki; Itoh, Yoshifumi; Ellis, Dawn M.; Ross, Harold O; Wiswall, Barbara H.; Murphy, Kathleen; Hillman, Milton C.; Hollis, Gregory; Newton, Robert; Magolda, Ronald L.; Trzaskos, James M.; Arner, Elizabeth C.

doi:10.1126/science.284.5420.1664

Cited by 658 publications

(493 citation statements)

References 26 publications

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“…The aggrecanases ADAM-TS4 and ADAM-TS5 are considered to be the principal proteinases responsible for cartilage proteoglycan degradation, and these enzymes contain the typical furin recognition motif (9,10). This study shows that the addition of a furin inhibitor to resorbing cartilage can partially block the breakdown of the proteoglycan matrix.…”

Section: Discussionmentioning

confidence: 79%

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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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Section: Discussionmentioning

confidence: 79%

“…MT1-MMP, MT3-MMP, and MMP-11 can all be activated by furin (31)(32)(33). In addition, the aggrecanases ADAM-TS4 and ADAM-TS5 contain this furin cleavage site (9,10), and the pro-domain of ADAM-TS4 can be removed by furin (34). Furin has been detected in normal cartilage, and elevated levels are found in osteoarthritic cartilage (35).…”

mentioning

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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“…The same study also showed upregulation of the aggrecanases ADAMTS-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) by IL-1. These proteins belong to the disintegrin and metalloprotease with thrombospondin motifs family (61), and are the only enzymes that have been shown to cleave aggrecan at a site that generates the Glu373-Ala374 fragments (62,63) seen in interleukin-1 stimulated bovine explant cultures (64) and human synovial fluid of OA patients (65).…”

Section: Models Of Osteoarthritis In Articular Cartilagementioning

confidence: 99%

Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage

et al. 2006

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In this article, both sodium magnetic resonance (MR) and T 1r relaxation mapping aimed at measuring molecular changes in cartilage for the diagnostic imaging of osteoarthritis are reviewed. First, an introduction to structure of cartilage, its degeneration in osteoarthritis (OA) and an outline of diagnostic imaging methods in quantifying molecular changes and early diagnostic aspects of cartilage degeneration are described. The sodium MRI section begins with a brief overview of the theory of sodium NMR of biological tissues and is followed by a section on multiple quantum filters that can be used to quantify both bi-exponential relaxation and residual quadrupolar interaction. Specifically, (i) the rationale behind the use of sodium MRI in quantifying proteoglycan (PG) changes, (ii) validation studies using biochemical assays, (iii) studies on human OA specimens, (iv) results on animal models and (v) clinical imaging protocols are reviewed. Results demonstrating the feasibility of quantifying PG in OA patients and comparison with that in healthy subjects are also presented. The section concludes with the discussion of advantages and potential issues with sodium MRI and the impact of new technological advancements (e.g. ultra-high field scanners and parallel imaging methods). In the theory section on T 1r , a brief description of (i) principles of measuring T 1r relaxation, (ii) pulse sequences for computing T 1r relaxation maps, (iii) issues regarding radio frequency power deposition, (iv) mechanisms that contribute to T 1r in biological tissues and (v) effects of exchange and dipolar interaction on T 1r dispersion are discussed. Correlation of T 1r relaxation rate with macromolecular content and biomechanical properties in cartilage specimens subjected to trypsin and cytokineinduced glycosaminoglycan depletion and validation against biochemical assay and histopathology are presented. Experimental T 1r data from osteoarthritic specimens, animal models, healthy human subjects and as well from osteoarthritic patients are provided. The current status of T 1r relaxation mapping of cartilage and future directions is also discussed. Copyright # 2006 John Wiley & Sons, Ltd. KEYWORDS: cartilage; arthritis; spin-lock; T1rho; sodium; MRI OSTEOARTHRITIS Osteoarthritis (OA) affects more than half of the population above the age of 65 (1,2) and has a significant negative impact on the quality of life of elderly individuals (3). The economic costs in the USA from OA have been estimated to be more than 1% of the gross domestic product (4). OA is now increasingly viewed as a metabolically active joint disorder of diverse etiologies. The biochemistry of the disease is characterized by the following changes in cartilage: reduced proteoglycan (PG) concentration, possible changes in the size of collagen fibril and aggregation of PG, increased water content and increased rate of synthesis and degradation of matrix macromolecules. The earliest changes in the cartilage due to OA result in a partial breakdown in the proteoglyc...

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“…However, 2 defined sites in the interglobular domain are thought to play an important role in normal and OA cartilage (8,9): the so-called MMP site (Asn 341 -Phe 342 ) (10), at which cleavage by many MMPs and in particular stromelysin (MMP-3) is described (10)(11)(12), and the so-called aggrecanase site (Glu 373 -Ala 374 ) (13)(14)(15)(16). For the latter site, enzymes such as aggrecanase 1 (ADAM-TS4) (17,18) and aggrecanase 2 (ADAM-TS5) (19), as well as MMP-14 (20) and more recently ADAM-TS1 (21), are thought to be responsible. At least, all these enzymes have been shown to cleave aggrecan correspondingly and to be expressed in articular chondrocytes in vivo or in vitro (22,23).…”

mentioning

confidence: 99%

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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Purification and Cloning of Aggrecanase-1: A Member of the ADAMTS Family of Proteins

Cited by 658 publications

References 26 publications

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

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

Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage

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

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Purification and Cloning of Aggrecanase-1: A Member of the ADAMTS Family of Proteins

Cited by 658 publications

References 26 publications

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

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

Sodium and T1ρ MRI for molecular and diagnostic imaging of articular cartilage

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

Contact Info

Product

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Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage