Aggrecan is degraded by matrix metalloproteinases in human arthritis. Evidence that matrix metalloproteinase and aggrecanase activities can be independent.

Fosang, Amanda J.; Maciewicz, Rose A.

doi:10.1172/jci119040

Cited by 189 publications

(160 citation statements)

References 49 publications

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“…Whereas it appears from the present studies that aggrecanase is the primary proteolytic activity responsible for aggrecan cleavage in cartilage, MMP-generated aggrecan metabolites have been shown to occur in arthritic human knee-joint synovial fluids [5,38]. Since no evidence for MMP-generated aggrecan catabolism could be found in the present study using normal articular cartilage of bovine or porcine origin, cartilage derived from latestage human OA knees (n l 3) was evaluated.…”

Section: Aggrecan Catabolism In Osteoarthritic (Oa) Human Articular Cmentioning

confidence: 78%

“…Detection of this MMP-generated metabolite in only one of the three samples tested correlates with the detection of a similarly sized aggrecan catabolite, initiating with the sequence FFG …, in approx. 50 % of arthritic synovial fluid samples [38]. In contrast with normal cartilage, IL-1 stimulation in OA human cartilage has been shown to significantly enhance the secretion of MMPs and decrease the synthesis of both TIMP-1 and TIMP-2 [39].…”

Section: Aggrecan Catabolism In Osteoarthritic (Oa) Human Articular Cmentioning

confidence: 99%

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Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

Little

Flannery

Hughes

et al. 1999

Biochemical Journal

115

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The importance of aggrecanase versus matrix metalloproteinase (MMP) enzymic activities in the degradation of aggrecan in normal and osteoarthritic (OA) articular cartilage in vitro was studied in order to further our understanding of the potential role of these two enzyme activities in aggrecan catabolism during the pathogenesis of cartilage degeneration. Porcine and bovine articular cartilage was maintained in explant culture for up to 20 days in the presence or absence of the catabolic stimuli retinoic acid, interleukin-1 or tumour necrosis factor-α. Release of proteoglycan from cartilage was measured as glycosaminoglycan (GAG) release using a colorimetric assay. Analysis of proteoglycan degradation products, both released into culture media and retained within the cartilage matrix, was performed by Western blotting using antibodies specific for the N- and C-terminal neoepitopes generated by aggrecanase- and MMP-related catabolism of the interglobular domain of the aggrecan core protein (IGD). In addition, studies determining the mRNA expression for MMP-3 and MMP-13 in these same cultures were undertaken. These analyses indicated that all three catabolic agents stimulated the release of > 80% of the GAG from the articular cartilage over 4 days. The degree of GAG release corresponded to an increase in aggrecanase-generated aggrecan catabolites released into the media and retained within the cartilage. Importantly, there was no evidence for the release of MMP-generated aggrecan metabolites into the medium, nor the accumulation of MMP-generated catabolites within the tissue in these same cultures. Expression of the mRNAs for two MMPs known to be capable of degrading the aggrecan IGD, MMP-3 and MMP-13, was detected. However, increased expression of these MMPs was not correlated with aggrecan degradation. Analyses using porcine cartilage, cultured with or without catabolic stimulation for 12 h to 20 days, indicated that primary cleavage of the IGD by aggrecanase was responsible for release of aggrecan metabolites at both the early and late time points of culture. Cultures of late-stage OA human articular cartilage samples indicated that aggrecanase activity was upregulated in the absence of catabolic stimulation when compared with normal porcine or bovine cartilage. In addition, even in this late-stage degenerate cartilage, aggrecanase and not MMP activity was responsible for the release of the majority of aggrecan from the cartilage. This study demonstrates that the release of aggrecan from both normal and OA cartilage in response to catabolic stimulation in vitro involves a primary cleavage by aggrecanase and not MMPs.

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Section: Aggrecan Catabolism In Osteoarthritic (Oa) Human Articular Cmentioning

confidence: 78%

Section: Aggrecan Catabolism In Osteoarthritic (Oa) Human Articular Cmentioning

confidence: 99%

Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

Little

Flannery

Hughes

et al. 1999

Biochemical Journal

115

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“…Plates were washed with a solution of 0.5% (volume/volume) Tween 20 in 0.8% (weight/volume) NaCl and then blocked overnight at 4°C with 0.2% (w/v) BSA in 50 mM Tris, 0.2% (v/v) Tween, and 0.002% (w/v) thimerosal, pH 7.5. Prior to the assay, SF samples were digested overnight at 37°C with 5 units/ml testicular hyaluronidase (44) After washing, the peroxidase substrate tetramethylbenzidine (200 l) was added to the wells, and the plates were incubated at room temperature for 15 minutes. The peroxidase reaction was stopped with 1.0M sulfuric acid (100 l per well), and the optical density was measured at 450 nm.…”

Section: Methodsmentioning

confidence: 99%

The release of crosslinked peptides from type II collagen into human synovial fluid is increased soon after joint injury and in osteoarthritis

Lohmander¹,

Atley²,

Pietka³

et al. 2003

Arthritis & Rheumatism

234

165

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Objective. To determine concentrations of crosslinked C-telopeptide fragments of type II collagen (CTX-II) in synovial fluid (SF) from patients with joint injury, osteoarthritis (OA), or other knee arthritides.Methods. Two study groups were used: a crosssectional group, which included healthy-knee volunteers (reference group [REF]) and patients with pseudogout (PPA), an anterior cruciate ligament tear with or without a meniscus tear (INJ), or primary knee OA (POA); and a longitudinal group, which included patients with arthroscopic cartilage changes or septic arthritis. CTX-II was quantified by competition enzyme-linked immunosorbent assay (ELISA) based on a monoclonal antibody that recognized the C-terminus of the peptide EKGPDP as a proteolytic neoepitope. Aggrecan fragments, matrix metalloproteinases 1 and 3, and tissue inhibitor of metalloproteinases 1 were determined by ELISAs.Results. Concentrations of CTX-II in SF were higher in patients with PPA, INJ, and POA than in the REF group (P < 0.001). After joint injury, mean levels of CTX-II in SF were increased above REF levels at all time intervals (P < 0.001), and were highest within hours after trauma. In those in the longitudinal study group with joint cartilage damage, variation coefficients for CTX-II were 81% (between patients) and 64% (within patient), monitored over 1 year. In a patient with septic arthritis, SF CTX-II increased at the onset of symptoms, and peaked 30-fold higher than the baseline. Concentrations of all biomarkers decreased with successful treatment.Conclusion. This is the first report to describe the release into SF of soluble molecular fragments specific for the degradation of mature, crosslinked, type II collagen (CII) in human OA and joint injury. The results provide strong evidence that the integrity of the CII network of cartilage is compromised soon after joint injury and in arthritis. This early degradation of CII may represent an important treatment target.Osteoarthritis (OA) and joint injury are characterized by remodeling and degradation of cartilage, bone, and other joint tissues. The normally very slow turnover rate of cartilage matrix (1) is increased, as observed by several techniques in both animal OA models and human OA. Phasic changes in both synthesis and degradation of collagen and other matrix molecules (2-6) are associated with altered tissue structure and material properties (7-9).Increased joint tissue turnover after injury and in OA can be detected by a release of molecules and molecular fragments into synovial fluid (SF), blood, and urine. For example, the stimulated synthesis of type II collagen (CII) results in higher levels of CII C-propeptide in SF (10,11). Stimulated aggrecan synthesis results in more aggrecan fragments carrying the 846 epitope (12). Higher synovial concentrations of matrix metalloproteinases (MMPs), such as MMP-1 and MMP-3, and proteinase activity after joint injury and in OA are consistent with the observed expression of these

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“…The primary substrate for MMPs on the aggrecan core protein is within the interglobular domain (IGD) at the VIPEN 360 -361 FFG bond (the equivalent substrate in bovine aggrecan is VDIPES 360 -361 FFG) . Importantly, MMP-mediated aggrecan catabolism appears to operate independent of aggrecanases and is thought to be a quantitatively minor mechanism of aggrecan degradation in injured or osteoarthritic cartilage (Fosang, et al, 1996;Sandy and Verscharen, 2001). …”

Section: Introductionmentioning

confidence: 99%

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

et al. 2007

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Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase-or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors which were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP-and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the loss of dynamic compression and shear moduli was delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

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Aggrecan is degraded by matrix metalloproteinases in human arthritis. Evidence that matrix metalloproteinase and aggrecanase activities can be independent.

Cited by 189 publications

References 49 publications

Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro

The release of crosslinked peptides from type II collagen into human synovial fluid is increased soon after joint injury and in osteoarthritis

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

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