Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2016

Open Access 01-12-2016 | Research article

Aggrecan heterogeneity in articular cartilage from patients with osteoarthritis

Authors: John S. Mort, Yeqing Geng, William D. Fisher, Peter J. Roughley

Published in: BMC Musculoskeletal Disorders | Issue 1/2016

Login to get access

Abstract

Background

Aggrecan degradation is the hallmark of cartilage degeneration in osteoarthritis (OA), though it is unclear whether a common proteolytic process occurs in all individuals.

Methods

Aggrecan degradation in articular cartilage from the knees of 33 individuals with OA, who were undergoing joint replacement surgery, was studied by immunoblotting of tissue extracts.

Results

Matrix metalloproteinases (MMPs) and aggrecanases are the major proteases involved in aggrecan degradation within the cartilage, though the proportion of aggrecan cleavage attributable to MMPs or aggrecanases was variable between individuals. However, aggrecanases were more associated with the increase in aggrecan loss associated with OA than MMPs. While the extent of aggrecan cleavage was highly variable between individuals, it was greatest in areas of cartilage adjacent to sites of cartilage erosion compared to sites more remote within the same joint. Analysis of link protein shows that in some individuals additional proteolytic mechanisms must also be involved to some extent.

Conclusions

The present studies indicate that there is no one protease, or a fixed combination of proteases, responsible for cartilage degradation in OA. Thus, rather than targeting the individual proteases for OA therapy, directing research to techniques that control global protease generation may be more productive.
Literature
1.
2.
Doege KJ, Sasaki M, Kimura T, Yamada Y. Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms. J Biol Chem. 1991;266:894–902.PubMed
3.
4.
Urban JPG, Maroudas A, Bayliss MT, Dillon J. Swelling pressures of proteoglycans at the concentrations found in cartilaginous tissues. Biorheology. 1979;16:447–64.PubMed
5.
Roughley PJ, White RJ. Age-related changes in the structure of the proteoglycan subunits from human articular cartilage. J Biol Chem. 1980;255:217–24.PubMed
6.
Jowitt TA, Murdoch AD, Baldock C, Berry R, Day JM, Hardingham TE. Order within disorder: Aggrecan chondroitin sulphate-attachment region provides new structural insights into protein sequences classified as disordered. Proteins. 2010;78:3317–27.PubMedCentralCrossRefPubMed
7.
Mort JS, Flannery CR, Makkerh J, Krupa JC, Lee ER. The use of anti-neoepitope antibodies for the analysis of degradative events in cartilage and the molecular basis for neoepitope specificity. Biochem Soc Symp. 2003;70:107–14.CrossRefPubMed
8.
Maehara H, Suzuki K, Sasaki T, Oshita H, Wada E, Inoue T, et al. G1-G2 aggrecan product that can be generated by m-calpain on truncation at Ala709-Ala710 is present abundantly in human articular cartilage. J Biochem. 2007;141:469–77.CrossRefPubMed
9.
Chamberland A, Wang E, Jones AR, Collins-Racie LA, LaVallie ER, Huang Y, et al. Identification of a novel HtrA1-susceptible cleavage site in human aggrecan. J Biol Chem. 2009;284:27352–9.PubMedCentralCrossRefPubMed
10.
Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta. 1824;2012:133–45.
11.
12.
Durigova M, Troeberg L, Nagase H, Roughley PJ, Mort JS. Involvement of ADAMTS5 and hyaluronidase in aggrecan degradation and release form OSM-stimulated cartilage. Eur Cell Mater. 2011;21:31–45.PubMedCentralPubMed
13.
Fushimi K, Troeberg L, Nakamura H, Lim NH, Nagase H. Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity. J Biol Chem. 2008;283:6706–16.CrossRefPubMed
14.
Larsson S, Englund M, Struglics A, Lohmander LS. The association between changes in synovial fluid levels of ARGS-aggrecan fragments, progression of radiographic osteoarthritis and self-reported outcomes: a cohort study. Osteoarthritis Cartilage. 2012;20:388–95.CrossRefPubMed
15.
Struglics A, Hansson M. MMP proteolysis of the human extracellular matrix protein aggrecan is mainly a process of normal turnover. Biochem J. 2012;446:213–23.CrossRefPubMed
16.
Larsson S, Englund M, Struglics A, Lohmander LS. Association between synovial fluid levels of aggrecan ARGS fragments and radiographic progression in knee osteoarthritis. Arthritis Res Ther. 2010;12:R230.PubMedCentralCrossRefPubMed
17.
18.
Sztrolovics R, White RJ, Roughley PJ, Mort JS. The mechanism of aggrecan release from cartilage differs with tissue origin and the agent used to stimulate catabolism. Biochem J. 2002;362:465–72.PubMedCentralCrossRefPubMed
19.
20.
Roughley PJ, Melching LI, Heathfield TF, Pearce RH, Mort JS. The structure and degradation of aggrecan in human intervertebral disc. Eur Spine J. 2006;15 Suppl 15:326–32.PubMedCentralCrossRef
21.
Caterson B, Christner JE, Baker JR, Couchman JR. Production and characterization of monoclonal antibodies directed against connective tissue proteoglycan. Fed Proc. 1985;44:386–93.PubMed
22.
Farndale RW, Buttle DJ, Barrett AJ. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta. 1986;833:173–7.CrossRef
23.
24.
Björnsson S. Size-dependent separation of proteoglycans by electrophoresis in gels of pure agarose. Anal Biochem. 1993;210:292–8.CrossRefPubMed
25.
Karlsson M, Edfors-Lilja I, Björnsson S. Binding and detection of glycosaminoglycans immobilized on membranes treated with cationic detergents. Anal Biochem. 2000;286:51–8.CrossRefPubMed
26.
McLean IW, Nakane PK. Periodate-lysine-paraformaldehyde fixative. A new fixation for immunoelectron microscopy. J Histochem Cytochem. 1974;22:1077–83.CrossRefPubMed
27.
Lee ER, Lamplugh L, Leblond CP, Mordier S, Magny M-C, Mort JS. Immunolocalization of the cleavage of the aggrecan core protein at the Asn341-Phe342 bond, as an indicator of the location of the metalloproteinases active in the lysis of the rat growth plate. Anat Rec. 1998;252:117–32.CrossRefPubMed
28.
Lee ER, Lamplugh L, Davoli MA, Beauchemin A, Chan K, Mort JS, et al. Enzymes active in the areas undergoing cartilage resorption during the development of the secondary ossification center in the tibiae of rats aged 0–21 days: I. Two groups of proteinases cleave the core protein of aggrecan. Dev Dyn. 2001;222:52–70.CrossRefPubMed
29.
Rodriguez E, Roland SK, Plaas A, Roughley PJ. The glycosaminoglycan attachment regions of human aggrecan. J Biol Chem. 2006;281:18444–50.CrossRefPubMed
30.
Nguyen Q, Murphy G, Roughley PJ, Mort JS. Proteoglycan aggregate degradation by a cartilage metalloproteinase. Evidence for the involvement of stromelysin in the generation of link protein heterogeneity in situ. Biochem J. 1989;259:61–7.PubMedCentralCrossRefPubMed
31.
Durigova M, Roughley PJ, Mort JS. Mechanism of proteoglycan aggregate degradation in cartilage stimulated with oncostatin M. Osteoarthritis Cartilage. 2008;16:98–104.CrossRefPubMed
32.
Lotz MK, Kraus VB. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther. 2010;12:211.PubMedCentralCrossRefPubMed
33.
latridis JC, Godburn K, Wuertz K, Alini M, Roughley PJ. Region-dependent aggrecan degradation patterns in the rat intervertebral disc are affected by mechanical loading in vivo. Spine. 2011;36:203–9.CrossRefPubMed
34.
Struglics A, Larsson S, Hansson M, Lohmander LS. Western blot quantification of aggrecan fragments in human synovial fluid indicates differences in fragment patterns between joint diseases. Osteoarthritis Cartilage. 2009;17:497–506.CrossRefPubMed
35.
Nguyen Q, Liu J, Roughley PJ, Mort JS. Link protein as a monitor in situ of endogenous proteolysis in human articular cartilage. Biochem J. 1991;278:143–7.PubMedCentralCrossRefPubMed
36.
Dejica VM, Mort JS, Laverty S, Percival MD, Antoniou J, Zukor DJ, et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am J Pathol. 2008;173:161–9.PubMedCentralCrossRefPubMed
37.
Clark IM, Parker AE. Metalloproteinases: their role in arthritis and potential as therapeutic targets. Expert Opin Ther Targets. 2003;7:19–34.CrossRefPubMed
38.
Bondeson J. Are we moving in the right direction with osteoarthritis drug discovery? Expert Opin Ther Targets. 2011;15:1355–68.CrossRefPubMed
Metadata
Title
Aggrecan heterogeneity in articular cartilage from patients with osteoarthritis
Authors
John S. Mort
Yeqing Geng
William D. Fisher
Peter J. Roughley
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2016
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-016-0944-8

Other articles of this Issue 1/2016

BMC Musculoskeletal Disorders 1/2016 Go to the issue

Research article

Analysis of trabecular bone microstructure in osteoporotic femoral heads in human patients: in vivo study using multidetector row computed tomography

Research article

Establishment of a preclinical ovine screening model for the investigation of bone tissue engineering strategies in cancellous and cortical bone defects

Research article

The prevalence of intraspinal anomalies in infantile and juvenile patients with “presumed idiopathic” scoliosis: a MRI-based analysis of 504 patients

Research article

Predictors of return to work following motor vehicle related orthopaedic trauma

Research article

Non-fusion procedure using PEEK rod systems for lumbar degenerative diseases: clinical experience with a 2-year follow-up

Research article

Analysis of the correlative factors in the selection of interbody fusion cage height in transforaminal lumbar interbody fusion