title: Tenascin-C fragments are endogenous inducers of cartilage matrix degradation.
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.
authors.affiliation: Department of Biomedical Sciences, St George's, University of London, Cranmer Terrace, London SW17 ORE, UK. nsofat@sgul.ac.uk
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sofat
authors.forename: Saralili Dipa
authors.initials: SD
authors.lastname: Robertson
authors.forename: Monika
authors.initials: M
authors.lastname: Hermansson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jones
authors.forename: Philip
authors.initials: P
authors.lastname: Mitchell
authors.forename: Robin
authors.initials: R
authors.lastname: Wait
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010450:Endopeptidases / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D023421:Models, Animal; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine; D019063:Tenascin / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D006025:Glycosaminoglycans; D010446:Peptide Fragments; D019063:Tenascin; D010450:Endopeptidases; D020782:Matrix Metalloproteinases; C083641:aggrecanase