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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Rheumatology International
Published in: Rheumatology International 9/2012

Open Access 01-09-2012 | Original Article

Tenascin-C fragments are endogenous inducers of cartilage matrix degradation

Authors: Nidhi Sofat, Saralili Dipa Robertson, Monika Hermansson, Jonathan Jones, Philip Mitchell, Robin Wait

Published in: Rheumatology International | Issue 9/2012

Login to get access

Abstract

Cartilage destruction is a hallmark of osteoarthritis (OA) and is characterized by increased protease activity resulting in the degradation of critical extracellular matrix (ECM) proteins essential for maintaining cartilage integrity. Tenascin-C (TN-C) is an ECM glycoprotein, and its expression is upregulated in OA cartilage. We aimed to investigate the presence of TN-C fragments in arthritic cartilage and establish whether they promote cartilage degradation. Expression of TN-C and its fragments was evaluated in cartilage from subjects undergoing joint replacement surgery for OA and RA compared with normal subjects by western blotting. The localization of TN-C in arthritic cartilage was also established by immunohistochemistry. Recombinant TN-C fragments were then tested to evaluate which regions of TN-C are responsible for cartilage-degrading activity in an ex vivo cartilage explant assay measuring glycosaminoglycan (GAG) release, aggrecanase and matrix metalloproteinase (MMP) activity. We found that specific TN-C fragments are highly upregulated in arthritic cartilage. Recombinant TN-C fragments containing the same regions as those identified from OA cartilage mediate cartilage degradation by the induction of aggrecanase activity. TN-C fragments mapping to the EGF-L and FN type III domains 3–8 of TN-C had the highest levels of aggrecan-degrading ability that was not observed either with full-length TN-C or with other domains of TN-C. TN-C fragments represent a novel mechanism for cartilage degradation in arthritis and may present new therapeutic targets for the inhibition of cartilage degradation.
Literature
1.
2.
3.
Mankin HJ, Lippiello L (1971) Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. J Bone Joint Surg Am 52:424–434
4.
Goldring SR, Goldring MB (2004) The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthop Relat Res 427:S27–S36PubMedCrossRef
5.
Nagase H, Kashiwagi M (2003) Aggrecanases and cartilage matrix degradation. Arthritis Res Ther 5:94–103PubMedCrossRef
6.
Kurz B, Jin M, Patwari P, Cheng DM, Lark MW, Grodzinsky AJ (2001) Biosynthetic response and mechanical properties of articular cartilage after injurious compression. J Orthop Res 19:1140–1146PubMedCrossRef
7.
Hunter DJ (2011) Pharmacologic therapy for osteoarthritis—the era of disease modification. Nat Rev Rheumatol 7(1):13–22PubMedCrossRef
8.
Okada Y (2001) Proteinases and matrix degradation. In: Ruddy S, Harris ED, Sledge C (eds) Kelley’s textbook of rheumatology. Saunders, Philadelphia, pp 55–73
9.
Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang AJ (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434:648–652PubMedCrossRef
10.
Lark MW, Bayne EK, Flanagan J, Harper CF, Hoerrner LA, Hutchinson NI, Singer I, Donatelli SA, Weidner JR, Williams HR, Mumford RA, Lohmander LS (1997) Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. J Clin Invest 100:93–106PubMedCrossRef
11.
Dodge GR, Poole AR (1989) Immunohistochemical detection and immunochemical analysis of type II collagen degradation in human normal, rheumatoid, and osteoarthritic articular cartilages and in explants of bovine articular cartilage cultured with interleukin 1. J Clin Invest 83:647–661PubMedCrossRef
12.
Aigner T, Zien A, Gehrsitz A, Gebhard PM, Mckenna L (2001) Anabolic and catabolic gene expression pattern analysis in normal versus osteoarthritic cartilage using complementary DNA-array technology. Arthritis Rheum 44:2777–2789PubMedCrossRef
13.
Lee JH, Fitzgerald JB, Dimicco MA, Grodzinsky AJ (2005) Mechanical injury of cartilage explants causes specific time-dependent changes in chondrocyte gene expression. Arthritis Rheum 52:2386–2395PubMedCrossRef
14.
Loening AM, James IE, Levenston ME, Badger AM, Frank EH, Kurz B, Nuttall ME, Hung HH, Blake SM, Grodzinsky AJ, Lark MW (2000) Injurious mechanical compression of bovine articular cartilage induces chondrocyte apoptosis. Arch Biochem Biophys 381:205–212PubMedCrossRef
15.
Fichter M, Korner U, Schomburg J, Jennings L, Cole AA, Mollenhauer J (2006) Collagen degradation products modulate matrix metalloproteinase expression in cultured articular chondrocytes. J Orthop Res 24(1):63–70PubMedCrossRef
16.
Heathfield TF, Onnerfjord P, Dahlberg L, Heinegard D (2004) Cleavage of fibromodulin in cartilage explants involves removal of the N-terminal tyrosine sulfate-rich region by proteolysis at a site that is sensitive to matrix metalloproteinase-13. J Biol Chem 279(8):6286–6295PubMedCrossRef
17.
Homandberg GA, Meyers R, Xie DL (1992) Fibronectin fragments cause chondrolysis of bovine articular cartilage slices in culture. J Biol Chem 267:3597–3604PubMed
18.
Knudson W, Casey B, Nishida Y, Eger W, Kuettner KE, Knudson CB (2000) Hyaluronan oligosaccharides perturb cartilage matrix homeostasis and induce chondrocytic chondrolysis. Arthritis Rheum 43:1165–1174PubMedCrossRef
19.
Jones PL, Jones FS (2000) Tenascin-C in development and disease: gene regulation and cell function. Matrix Biol 19:581–596PubMedCrossRef
20.
Salter DM (1993) Tenascin is increased in cartilage and synovium from arthritic knees. Br J Rheumatol 32:780–786PubMedCrossRef
21.
Chevalier X, Groult N, Larget Piet B, Zardi L, Hornebeck W (1994) Tenascin distribution in articular cartilage from normal subjects and from patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 37(7):1013–1022PubMedCrossRef
22.
Cutolo M, Picasso M, Ponassi M, Sun MZ, Balza E (1992) Tenascin and fibronectin distribution in human normal and pathologic synovium. J Rheumatol 19:1439–1447PubMed
23.
McCachren SS, Lightner VA (1992) Expression of human tenascin in synovitis and its regulation by interleukin-1. Arthritis Rheumatism 35:1185–1196PubMedCrossRef
24.
Hasegawa M, Nakoshi Y, Muraki M, Sudo A, Kinoshita N, Yoshida T, Uchida A (2007) Expression of large tenascin-c splice variants in synovial fluid of patients with rheumatoid arthritis. J Orthop Res 25:563–568PubMedCrossRef
25.
Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, Drexler S, Sofat N, Kashiwagi M, Orend G, Brennan F, Foxwell B (2009) Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15(7):774–781PubMedCrossRef
26.
Okamura N, Hasegawa M, Nakoshi Y, Iino T, Sudo A, Imanaka-Yoshida K, Yoshida T, Uchida A (2010) Deficiency of tenascin-C delays articular cartilage repair in mice. Osteoarthr Cartilage 18(6):839–848
27.
Wykcoff D, Rodbard A, Chrambach A (1977) Polyacrylamide gel electrophoresis in sodium dodecyl sulfate-containing buffers using multiphasic buffer systems: properties of the stack, valid Rf-measurement, and optimized procedure. Anal Biochem 78:459–482CrossRef
28.
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685PubMedCrossRef
29.
Meyer TS, Lambert BL (1965) Use of Coomassie brilliant blue R250 for the electrophoresis of microgram quantities of parotid saliva proteins on acrylamide-gel strips. Biochim Biophys Acta 107:144–145PubMedCrossRef
30.
Shevchenko A, Wilm M, Vorm O, Mann M (1980) Mass spectrometric sequencing of proteins silver stained polyacrylamide gels. Anal Chem 68:850–858CrossRef
31.
Gendron C, Kashiwagi M, Hughes C, Caterson B, Nagase H (2003) TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors. FEBS Lett 555:431–436PubMedCrossRef
32.
Farndale RW, Buttle DJ, Barrett AJ (1986) Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta 883:173–177PubMedCrossRef
33.
Sofat N (2009) Analysing the role of endogenous matrix molecules in the development of osteoarthritis. Int J Exp Pathol 90:463–479PubMedCrossRef
34.
Nakoshi Y, Hasegawa M, Akeda K, Iino T, Sudo A, Yoshida T, Uchida A (2010) Distribution and role of tenascin-C in human osteoarthritic cartilage. J Orthop Sci 15(5):666–673PubMedCrossRef
35.
Zhen EY, Brittain IJ, Laska DA, Mitchell PG, Sumer EU, Karsdal MA, Duffen KL (2008) Characterization of metalloproteinase cleavage products of human articular cartilage. Arthritis Rheum 58(8):2420–2431PubMedCrossRef
36.
Latijnhouwers MAHE, Bergers M, Veenhuis RT, Beekman B, Ankersmit-Ter Horst MFP, Schalkwijk J (1998) Tenascin-C degradation in chronic wounds is dependent on serine proteinase activity. Arch Dermatol Res 290:490–496PubMedCrossRef
37.
Wallner K, Li C, Shah PK, Wu K-J, Schwartz SM, Sharifi BG (2004) EGF-like domain of tenascin-C is proapoptotic for cultured smooth muscle cells. Arterioscler Thromb Vasc Biol 24:1416–1421PubMedCrossRef
38.
Prieto AL, Andersson-Fissone C, Crossin KL (1992) Characterization of multiple adhesive and counteradhesive domains in the extracellular matrix protein cytotactin. J Cell Biol 111:685–698CrossRef
39.
Spring J, Beck K, Chiquet-Ehrisman R (1989) Two contrary functions of tenascin: dissection of the active sites by recombinant tenascin fragments. Cell 59:325–334PubMedCrossRef
40.
Siri A, Knauper V, Veirana N, Caocci F, Murphy G, Zardi L (1995) Different susceptibility of small and large human tenascin-C isoforms to degradation by matrix metalloproteinases. J Biol Chem 270:8650–8654PubMedCrossRef
41.
Spring J, Beck K, Chiquet-Ehrisman R (1989) Two contrary functions of tenascin: dissection of the active sites by recombinant tenascin fragments. Cell 59:325–334PubMedCrossRef
42.
Weber P, Zimmerman DR, Winterhalter KH, Vaughan L (1995) Tenascin-C binds heparin by its fibronectin type III domain five. J Biol Chem 270:4619–4623PubMedCrossRef
43.
Day JM, Olin AI, Murdoch AD, Canfield A, Sasaki T, Timpl R, Hardingham TE, Aspberg A (2004) Alternative splicing in the aggrecan G3 domain influences binding interactions with tenascin-C and other extracellular matrix proteins. J Biol Chem 279:12511–12518PubMedCrossRef
44.
Echtermeyer F, Betrand J, Dreier R et al (2009) Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med 15(9):1072–1076PubMedCrossRef
45.
Salter DM, Hughes DE, Simpson R, Gardner DL (1992) Integrin expression by human articular chondrocytes. Br J Rheumatol 31:231–234PubMedCrossRef
46.
Zhang Q, Hui W, Litherland GJ et al (2008) Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis 67(11):1633–1641PubMedCrossRef
47.
Hashimoto G, Shimoda M, Okada Y (2004) ADAMTS4 (aggrecanase-1) interaction with the COOH-terminal domain of fibronectin inhibits proteolysis of aggrecan. J Biol Chem 279:32483–32491PubMedCrossRef
Metadata
Title
Tenascin-C fragments are endogenous inducers of cartilage matrix degradation
Authors
Nidhi Sofat
Saralili Dipa Robertson
Monika Hermansson
Jonathan Jones
Philip Mitchell
Robin Wait
Publication date
01-09-2012
Publisher
Springer-Verlag
Published in
Rheumatology International / Issue 9/2012
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-011-2067-8

Other articles of this Issue 9/2012

Rheumatology International 9/2012 Go to the issue

Original Article

Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study

Original Article

“Mutation negative” familial cold autoinflammatory syndrome (FCAS) in an 8-year-old boy: clinical course and functional studies

Original Article

Prevalence and clinical presentations of hepatitis C virus among patients admitted to the rheumatology ward

Original Article

Prevalence and correlates of suicidal ideation in SLE inpatients: Chinese experience

Original Article

Local tolerance of intraarticular administration of lornoxicam into the rabbit knee joint

Original Article

Disturbed Th17/Treg balance in patients with rheumatoid arthritis

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits