ADAMTS-5: The story so far

Fosang, Amanda J.; Rogerson, Fraser M.; East, Charlotte J.; Stanton, Heather

doi:10.22203/ecm.v015a02

Cited by 101 publications

(90 citation statements)

References 150 publications

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“…In general, ADAMTS-5 is constitutively expressed in human chondrocytes and synovial fibroblasts, whereas ADAMTS-4 expression is induced by proinflammatory cytokines (Fosang et al, 2008). The active forms of ADAMTS-4 were increased in synovial fluid samples from patients with active Lyme arthritis (Behera et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages

Li¹,

Du²,

Wang³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. We compared serum levels of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, matrix metalloproteinase (MMP)-1, and MMP-3 in patients with different stages of knee osteoarthritis (OA), and investigated the clinical significance of diagnosing OA in early stages. OA patients were divided into 2 groups: early OA group (44 cases), intermediate and advanced OA group (26 cases). The healthy control group included 30 samples. ADAMTS-4, ADAMTS-5, MMP-1, and MMP-3 levels in the serum were tested using an enzyme-linked immunosorbent assay. A protein-protein interaction network was constructed by seeding the significantly expressed marker, followed by Gene Ontology enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. ADAMTS-4 levels were significantly higher in patients at early stages of OA compared to intermediate or advanced OA and healthy controls. ADAMTS-5, MMP-1, and MMP-3 levels in intermediate and advanced-stage OA patients were significantly higher than those in early-stage OA patients and healthy controls. The proteinprotein interaction network showed that ADAMTS-4 participates in

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Section: Discussionmentioning

confidence: 99%

Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages

Li¹,

Du²,

Wang³

et al. 2014

Genet. Mol. Res.

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“…Aggrecan turnover within the extracellular matrix occurs due to the enhanced activity of endoproteinases such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 (3, 4) and 5 (5,6) as well as other matrix metalloproteinases (MMPs) (7)(8)(9)(10)(11). In addition to aggrecan, a significant loss of hyaluronan (HA) is also observed in human OA cartilage as compared with normal human cartilage (12,13).…”

mentioning

confidence: 99%

4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan Inhibition

Ishizuka

Askew

Ishizuka

et al. 2016

Journal of Biological Chemistry

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Depletion of the cartilage proteoglycan aggrecan is one of the earliest events that occurs in association with osteoarthritis. This loss is often accompanied by a coordinate loss in another glycosaminoglycan, hyaluronan. Chondrocytes experimentally depleted of cell-associated hyaluronan respond by switching to a pro-catabolic metabolism that includes enhanced production of endogenous inflammatory mediators and increased synthesis of matrix metalloproteinases. Hyaluronan turnover is also increased. Together, such a response provides for possible establishment of a self-perpetuating spiral of events that maintains or prolongs the pro-catabolic state. Chondrocytes or cartilage can also be activated by treatment with pro-inflammatory cytokines and mediators such as IL-1␤, TNF␣, LPS, fibronectin fragments, and hyaluronan oligosaccharides. To determine the mechanism of chondrocyte activation due to hyaluronan loss, a depletion method was required that did not include degrading the hyaluronan. In recent years, several laboratories have used the coumarin derivative, 4-methylumbelliferone, as a potent inhibitor of hyaluronan biosynthesis, due in part to its ability to sequester intracellular UDP-glucuronic acid and inhibition of hyaluronan synthase transcription. However, contrary to our expectation, although 4-methylumbelliferone was indeed an inhibitor of hyaluronan biosynthesis, this depletion did not give rise to an activation of chondrocytes or cartilage. Rather, 4-methylumbelliferone directly and selectively blocked gene products associated with the pro-catabolic metabolic state of chondrocytes and did so through a mechanism preceding and independent of hyaluronan inhibition. These data suggest that 4-methylumbelliferone has additional useful applications to block pro-inflammatory cell activation events but complicates how it is used for defining functions related to hyaluronan.The pronounced loss of aggrecan from articular cartilage is an early critical event associated with osteoarthritis (OA) 2 (1, 2). Aggrecan turnover within the extracellular matrix occurs due to the enhanced activity of endoproteinases such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 (3, 4) and 5 (5, 6) as well as other matrix metalloproteinases (MMPs) (7)(8)(9)(10)(11). In addition to aggrecan, a significant loss of hyaluronan (HA) is also observed in human OA cartilage as compared with normal human cartilage (12,13). A marked depletion of HA was also observed in articular cartilage damaged experimentally, such as in the anterior cruciate ligament transection model of OA (14) and a reduced-loading, splint immobilization model (15) in dogs. In our studies, cultured explants of human articular cartilage treated with IL-1␣ displayed a loss of HA within the superficial and upper middle layers of cartilage, the same layers in which aggrecan loss occurred (16). Other studies on cytokine-stimulated cartilage explants suggested that HA is lost from the cartilage (17,18), and other studies revealed that the HA is lost...

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“…TIMP-3 is the major endogenous inhibitor of aggrecanases known to date (for review, see ref. 5), and Timp3 -/-mice (age Ն6 months) exhibit cartilage destruction (14). In the study by Chia et al, no effects on Timp3 expression were observed under any conditions, although Timp1 levels were increased following surgery in either WT or Fgf2 -/-mice.…”

Section: Jelena Gavrilovicmentioning

confidence: 94%

“…5). Elegant studies in mouse models of arthritis have revealed that ADAMTS-5 is the key enzyme in aggrecan breakdown in this context (6,7).…”

Section: Jelena Gavrilovicmentioning

confidence: 99%

Fibroblast growth factor 2: A new key player in osteoarthritis

Gavrilović

2009

Arthritis & Rheumatism

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ADAMTS-5: The story so far

Cited by 101 publications

References 150 publications

Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages

Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages

4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan Inhibition

Fibroblast growth factor 2: A new key player in osteoarthritis

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