title: Inhibition of aggrecan turnover in short-term explant cultures of bovine tendon.
abstract: The large aggregating proteoglycan, aggrecan, better known for its physiological role in articular cartilage where it serves to facilitate resistance of compressive forces during joint articulation, is also present within the distinct functional regions of tendon (i.e., compressed/fibrocartilaginous and tensional). Previous studies demonstrate that an increased turnover of aggrecan occurs in tendon, which is mediated principally by the 'aggrecanases' and, as such, these proteinases may play an important role in the normal functioning of the tissue. In the present study, utilising bovine tendon explant culture systems, we demonstrated that aggrecanase-mediated tendon aggrecan turnover may be modulated by generic metalloproteinase inhibitors (i.e., the aggrecanase inhibitor, actinonin and the broad-spectrum MMP inhibitor, marimistat). As expected, no MMP-generated aggrecan catabolites were detected in the culture system, suggesting that tendon aggrecanases may be inhibited by marimistat. Furthermore, immunohistochemical analyses revealed that aggrecan metabolites are present in the endotenon, surrounding the collagen fibre bundles, suggesting that aggrecan may provide functions of water imbibement and resistance of reversible and repeated compressive loads manifest between the collagen fibres; these functions, in turn, may be associated with increased aggrecan turnover in this tissue. Thus, inhibition of tendon aggrecanases and consequently aggrecan turnover in this tissue, may be related to some of the deleterious effects observed in the tendons of patients undergoing drug therapy with broad-spectrum MMP inhibitors for cancer and arthritis.
authors.affiliation: School of Medicine, Swansea University, Singleton Park, Swansea, SA2 8PP, UK. s.g.rees@swansea.ac.uk
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Rees
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Waggett
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dent
authors.forename: Bruce
authors.initials: B
authors.lastname: Caterson
mesh_terms: D053674:Aggrecans / Q000378:metabolism*; D000818:Animals; D002356:Cartilage / Q000378:metabolism; D002417:Cattle; D018929:Cell Culture Techniques / Q000379:methods; D003094:Collagen / Q000378:metabolism; D003470:Culture Media / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D011509:Proteoglycans / Q000378:metabolism; D013710:Tendons / Q000166:cytology / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D003470:Culture Media; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D003094:Collagen; D010450:Endopeptidases; D020782:Matrix Metalloproteinases; C083641:aggrecanase