Link protein shows species variation in its susceptibility to proteolysis

Liu, J.; Cassidy, J. David; Allan, Adrian K.; Neame, Peter J.; Mort, John S.; Roughley, Peter J.

doi:10.1002/jor.1100100504

Cited by 15 publications

(6 citation statements)

References 40 publications

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“…To further define the identity, distribution and quantity of such fragments, monospecific antibodies were produced that recognize enzyme-generated neoepitopes that are not present in the native, uncleaved molecules. The MMP-generated neoepitope in link protein was thus detected in young cartilage, and with age and joint disease there was a reduction in this epitope (15). These data suggested that MMP degradation of link protein may be involved in normal matrix turnover and that further catabolic processes may be involved in link protein degradation with age.…”

Section: Introductionmentioning

confidence: 79%

Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints.

Lark¹,

Bayne²,

Flanagan³

et al. 1997

J. Clin. Invest.

436

283

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To examine the activity of matrix metalloproteinases (MMPs) and aggrecanase in control and diseased human articular cartilage, metabolic fragments of aggrecan were detected with monospecific antipeptide antibodies. The distribution and quantity of MMP-generated aggrecan G1 fragments terminating in VDIPEN 341 were compared with the distribution of aggrecanase-generated G1 fragments terminating in NITEGE 373 . Both types of G1 fragments were isolated from osteoarthritic cartilage. The sizes were consistent with a single enzymatic cleavage in the interglobular domain region, with no further proteolytic processing of these fragments. Both neoepitopes were also detected by immunohistochemistry in articular cartilage from patients undergoing joint replacement for osteoarthritis (OA), rheumatoid arthritis (RA), and in cartilage from adults with no known joint disease.In control specimens, the staining intensity for both G1 fragments increased with age, with little staining in cartilage from 22-wk-old fetal samples. There was also an increase with age in the extracted amount of MMP-generated neoepitope in relation to both aggrecan and collagen content, confirming the immunohistochemical results. After the age of 20-30 yr this relationship remained at a steady state. The staining for the MMP-generated epitope was most marked in control cartilage exhibiting histological signs of damage, whereas intense staining for the aggrecanase-generated fragment was often noted in adult cartilage lacking overt histological damage . Intense staining for both neoepitopes appeared in the more severely fibrillated, superficial region of the tissue.Intense immunostaining for both VDIPEN-and NITEGEneoepitopes was also detected in joint cartilage from patients with OA or RA. Cartilage in these specimens was significantly more degraded and high levels of staining for both epitopes was always seen in areas with extensive cartilage damage. The levels of extracted VDIPEN neoepitope relative to collagen or aggrecan in both OA and RA samples were similar to those seen in age-matched control specimens.Immunostaining for both types of aggrecan fragments was seen surrounding the cells but also further removed in the interterritorial matrix. In some regions of the tissue, both neoepitopes were found while in others only one was detected. Thus, generation and/or turnover of these specific catabolic aggrecan fragments is not necessarily coordinated. Our results are consistent with the presence in both normal and arthritic joint cartilage of proteolytic activity against aggrecan based on both classical MMPs and "aggrecanase.

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Section: Introductionmentioning

confidence: 79%

Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints.

Lark¹,

Bayne²,

Flanagan³

et al. 1997

J. Clin. Invest.

436

283

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“…Taken together, this signifies a relative deficiency in the LP content of aggregates in mature cartilage which can lead to a less stable interaction between aggrecan and HA in aggregates which are not fully LP stabilised [130]. The stability of aggregates in mature cartilage is likely to be further compromised by the age-related increase in degradative fragments of the free G1, LP [127,[131][132][133] and HA [134], which all can compete with intact aggrecan for binding sites on HA. The findings of Wells et al [127] demonstrate that the generally accepted model of aggregate formation in cartilage (one LP binding to both aggrecan and HA) is true for immature human cartilage but cannot be applied to adult cartilage, which has a heterogeneous population of complexes with a range of stabilities.…”

Section: Age-related Changesmentioning

confidence: 99%

Aggrecan, aging and assembly in articular cartilage

Dudhia

2005

Cell. Mol. Life Sci.

172

146

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The primary function of articular cartilage to act as a self-renewing, low frictional material that can distribute load efficiently at joints is critically dependent upon the composition and organisation of the extracellular matrix. Aggrecan is a major component of the extracellular matrix, forming high molecular weight aggregates necessary for the hydration of cartilage and to meet its weight-bearing mechanical demands. Aggregate assembly is a highly ordered process requiring the formation of a ternary complex between aggrecan, link protein and hyaluronan. There is extensive age-associated heterogeneity in the structure and molecular stoichiometry of these components in adult human articular cartilage, resulting in diverse populations of complexes with a range of stabilities that have implications for cartilage mechanobiology and integrity. Recent findings have demonstrated that aggrecan can form ligands with other matrix proteins. These findings provide new insights into mechanisms for aggregate assembly and functional protein networks in different cartilage compartments with maturation and aging.

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“…-3 varies among different species and cartilage sources; older cartilage may also contain link protein species with further proteolytic damage [20,21]. No evidence for the expression as protein of alternate spliced forms of link protein mRNA has been reported.…”

Section: Introductionmentioning

confidence: 99%

Human link protein gene: structure and transcription pattern in chondrocytes

Dudhia¹,

Bayliss²,

Hardingham³

1994

Biochemical Journal

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We have examined the genomic organization and the transcription unit for the human link protein gene from genomic clones and RNA prepared from human cartilage over a wide age range. Five exons cover the gene which is greater than 60 kbp. Primer extension and SI nuclease protection analysis revealed transcription initiation to be 315 bases upstream from the translation initiation codon in RNA derived from cartilage samples ranging from fetal to 53 years of age. The first exon size therefore is 289 bp and examination of the 5' flanking sequence indicated a lack of a TATA box in close proximity to the

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Link protein shows species variation in its susceptibility to proteolysis

Cited by 15 publications

References 40 publications

Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints.

Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints.

Aggrecan, aging and assembly in articular cartilage

Human link protein gene: structure and transcription pattern in chondrocytes

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