Increased vulnerability of postarthritic cartilage to a second arthritic insult: accelerated MMP activity in a flare up of arthritis

Meurs, Joyce B. J. van; Lent, P.L.E.M. van; Loo, A. A. J. van de; Holthuysen, A.E.M.; Bayne, Ellen K.; Singer, Irwin; Berg, Wim B. van den

doi:10.1136/ard.58.6.350

Cited by 32 publications

(16 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The C-terminal neoepitope DIPEN 341 ( Fig. 1c) has been immunolocalized in human articular and intervertebral disc cartilage (9,10) and in experimentally induced arthritis models in mice (13,14,(23)(24)(25)(26), providing evidence that MMPs directly degrade aggrecan in vivo.…”

mentioning

confidence: 98%

Generation and Novel Distribution of Matrix Metalloproteinase-derived Aggrecan Fragments in Porcine Cartilage Explants

Fosang

Stanton

Weeks

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

We have studied aggrecan catabolism mediated by matrix metalloproteinases (MMPs) in a porcine cartilage culture system. Using antibodies specific for DIPEN 341 Aggrecan is the major proteoglycan present in articular cartilage, and it is the molecule that endows cartilage with its intrinsic capacity to bear load and resist compression. This weight-bearing capacity is dependent on the structure and organization of collagen and aggrecan within the extracellular matrix. Normal turnover of aggrecan is a conservative process in which the rate of breakdown and release of fragments from the tissue does not exceed the rate at which it is replaced by newly synthesized molecules. In pathology, an increased rate of degradation results in a net loss of aggrecan, and the tissue becomes thin and mechanically weak.Aggrecan is lost from cartilage following proteolysis of the core protein. Aggrecanases are thought to be the enzymes primarily responsible for this proteolysis. Two ADAM 1 proteins with thrombospondin motifs, ADAMTS-4 (aggrecanase-1) (1) and ADAMTS-5 (aggrecanase-2, also known as ADAMTS-11) (2, 3) have been purified from bovine cartilage, and the corresponding human enzymes have been cloned and shown to exhibit the same specificity for aggrecan substrates as the purified bovine enzymes. The most widely documented activity of aggrecanase is hydrolysis of the Glu 373 2Ala 374 bond (numbering based on the human sequence) (4) in the interglobular domain (IGD) (Fig. 1c); however aggrecanases also cleave within highly conserved regions of the chondroitin sulfate attachment region (5, 6). Fragments resulting from aggrecanase action and containing the 374 ARGSV N terminus (Fig. 1c) have been detected in conditioned culture medium by sequence analysis of isolated fragments or by detection with specific neoepitope antibodies. Aggrecanase-derived 374 ARGSV fragments are the major aggrecan products found in synovial fluids from arthritis patients (7,8). Furthermore, the aggrecanase-derived ITEGE 373 neoepitope at the C terminus of the G1 domain has been detected in human (9, 10), bovine (11, 12), pig (12), and rat (11) cartilage and in mice with experimental arthritis (13,14).In addition to cleavage by aggrecanase, there is convincing evidence for the direct involvement of the matrix metalloproteinase (MMP) family of enzymes in aggrecanolysis, albeit at much lower levels. The specific products of MMP activity have been detected in vivo (10, 15, 16) and in vitro (17-19) by sequencing and more recently by cleavage site-specific neo-

show abstract

mentioning

confidence: 98%

Generation and Novel Distribution of Matrix Metalloproteinase-derived Aggrecan Fragments in Porcine Cartilage Explants

Fosang

Stanton

Weeks

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Proteolysis in the IGD releases the entire chondroitin sulfate and keratan sulfate-rich regions essential for the biomechanical properties of aggrecan, and is therefore thought to be the most detrimental for cartilage function. In pathology, proteolysis is driven mainly by aggrecanases, but there may also be some involvement of matrix metalloproteinases (MMPs) in late stage disease (1)(2)(3). "Aggrecanase" was first identified as a novel activity that cleaved the aggrecan core protein at the E 373 2 374 A bond in the IGD (4 -6) and at four specific sites in the CS-2 domain (5,6).…”

mentioning

confidence: 99%

ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan

East

Stanton

Golub

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

In the mouse, proteolysis in the aggrecan interglobular domain is driven by ADAMTS-5, and mice deficient in ADAMTS-5 catalytic activity are protected against aggrecan loss and cartilage damage in experimental models of arthritis. Here we show that despite ablation of ADAMTS-5 activity, aggrecanolysis can still occur at two preferred sites in the chondroitin sulfate-rich region. Retinoic acid was more effective than interleukin-1␣ (IL) in promoting cleavage at these sites in ADAMTS-5-deficient cartilage. These results suggest that cleavage at preferred sites in the chondroitin sulfate-rich region is mediated by ADAMTS-4 or an aggrecanase other than ADAMTS-5. Following retinoic acid or IL-1␣ stimulation of cartilage explants, aggrecan fragments in medium and extracts contained SELE 1279 or FREEE 1467 C-terminal sequences. Some SELE 1279 and FREEE 1467 fragments were retained in the cartilage, with intact G1 domains. Other SELE 1279 fragments were released into the medium and co-migrated with the 374 ALGS neoepitope, indicating they were aggrecanase-derived fragments. In contrast none of the FREEE 1467 fragments released into the medium co-migrated with the 374 ALGS neoepitope, suggesting that, despite their size, these fragments were not products of aggrecanase cleavage in the interglobular domain. ADAMTS-5, but not ADAMTS-1, -4, or -9, was up-regulated 8-fold by retinoic acid and 17-fold by IL-1␣ treatment. The data show that whereas ADAMTS-5 is entirely responsible for cleavage in the interglobular domain, cleavage in the chondroitin sulfate-rich region is driven either by ADAMTS-4, which compensates for loss of ADAMTS-5 in this experimental system, or possibly by another aggrecanase. The data show that there are differential aggrecanase activities with preferences for separate regions of the core protein.A feature of joint pathology in arthritis is destruction of articular cartilage. The major structural components of cartilage are type II collagen and the large aggregating proteoglycan, aggrecan. In healthy cartilage, type II collagen and aggrecan confer strength and compliance that enables this tissue to resist compressive forces. In arthritic diseases, the progressive degradation of aggrecan and type II collagen leads to cartilage erosion. Aggrecan has two globular domains, G1 and G2 at the N terminus, and a third globular domain, G3 at the C terminus. An extended sequence between the G2 and G3 domains is heavily substituted with keratan sulfate and chondroitin sulfate chains, organized into a distinct keratan sulfate-rich region and chondroitin sulfate-1 (CS-1) 2 and chondroitin sulfate-2 (CS-2) domains. An interglobular domain (IGD) of ϳ150 amino acids separates G1 from G2.The aggrecan IGD is highly sensitive to proteinases. Proteolysis in the IGD releases the entire chondroitin sulfate and keratan sulfate-rich regions essential for the biomechanical properties of aggrecan, and is therefore thought to be the most detrimental for cartilage function. In pathology, proteolysis is driven mainly by aggrecanases...

show abstract

“…Our previous in vitro studies suggested that MMPs are involved in the baseline turnover of aggrecan, whereas aggrecanases drive accelerated turnover. Other studies in mouse models of arthritis suggest that aggrecanases are involved in initiating early aggrecan loss and cartilage damage but that severe, late-stage disease may be MMP driven (74)(75)(76). The major aggrecanase in articular cartilage appears to be ADAMTS-5 (64).…”

mentioning

confidence: 99%

Matrix Metalloproteinases Are Not Essential for Aggrecan Turnover during Normal Skeletal Growth and Development

Little

Meeker

Hembry

et al. 2005

Molecular and Cellular Biology

View full text Add to dashboard Cite

The growth plate is a transitional region of cartilage and highly diversified chondrocytes that controls long bone formation. The composition of growth plate cartilage changes markedly from the epiphysis to the metaphysis, notably with the loss of type II collagen, concomitant with an increase in MMP-13; type X collagen; and the C-propeptide of type II collagen. In contrast, the fate of aggrecan in the growth plate is not clear: there is biosynthesis and loss of aggrecan from hypertrophic cartilage, but the mechanism of loss is unknown. All matrix metalloproteinases (MMPs) cleave aggrecan between amino acids N 341 and F 342 in the proteinase-sensitive interglobular domain (IGD), and MMPs in the growth plate are thought to have a role in aggrecanolysis. We have generated mice with aggrecan resistant to proteolysis by MMPs in the IGD and found that the mice develop normally with no skeletal deformities. The mutant mice do not accumulate aggrecan, and there is no significant compensatory proteolysis occurring at alternate sites in the IGD. Our studies reveal that MMP cleavage in this key region is not a predominant mechanism for removing aggrecan from growth plate cartilage.Endochondral ossification is the process by which bone is formed upon a cartilage template. It occurs in skeletal development, in fracture healing, and during bone growth at the growth plates and involves the transition from avascular cartilage, rich in type II collagen and aggrecan, to highly vascular bone, rich in type I collagen and mineral. During endochondral bone formation, prechondrogenic mesenchymal cells differentiate into chondrocytes, which proliferate and then mature into hypertrophic chondrocytes. The hypertrophic cartilage begins to calcify, the cartilage matrix is degraded and is invaded by blood vessels, the terminal hypertrophic chondrocytes apoptose, and bone matrix is deposited on the calcified cartilage trabeculae. This is a busy schedule of events in the growth plate, and their precise timing in relation to each other has not been clearly defined.The growth plate is a striking remodeling unit both anatomically and biochemically. Anatomically, it is bordered by the secondary center of ossification and epiphysis at one end and the bony metaphysis at the other. It comprises reserve, proliferative, prehypertrophic, and hypertrophic zones. Chondrocytes in the reserve zone are rounded and sparsely distributed, whereas chondrocytes in the proliferative zone are flattened and occupy approximately one-quarter of the tissue volume. Cells of the proliferative zone divide and arrange themselves into ordered columns separated by longitudinal septa. At the same time, they increase their secretion of matrix molecules so that around 75% of the tissue volume is cartilage matrix. In the hypertrophic zones, the cells retain their columnar organization and increase their metabolic activity. They enlarge by as much as 10-fold (28) so that matrix volume is reduced to approximately 40%, with cells occupying 60% of the tissue volume (5). Calcificat...

show abstract

Increased vulnerability of postarthritic cartilage to a second arthritic insult: accelerated MMP activity in a flare up of arthritis

Abstract: were found to be present in the cartilage before induction of a flare up. (Ann Rheum Dis 1999;58:350-356)

Cited by 32 publications

References 35 publications

Generation and Novel Distribution of Matrix Metalloproteinase-derived Aggrecan Fragments in Porcine Cartilage Explants

Generation and Novel Distribution of Matrix Metalloproteinase-derived Aggrecan Fragments in Porcine Cartilage Explants

ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan

Matrix Metalloproteinases Are Not Essential for Aggrecan Turnover during Normal Skeletal Growth and Development

Contact Info

Product

Resources

About