title: Inhibition of bovine nasal cartilage degradation by selective matrix metalloproteinase inhibitors.
abstract: N-terminal analysis of aggrecan fragments lost from bovine nasal cartilage cultured in the presence of recombinant human interleukin 1alpha revealed a predominant ARGSVIL sequence with an additional ADLEX sequence. Production of the ARGSVIL-containing fragments has been attributed to the action of a putative proteinase, aggrecanase. The minor sequence (ADLEX) corresponds to a new reported cleavage product; comparison of this sequence with the available partial sequence of bovine aggrecan indicates that this is the product of a cleavage occurring towards the C-terminus of the protein. Matrix metalloproteinase (MMP) inhibitors inhibited aggrecan loss from bovine nasal explants incubated in the presence of recombinant human interleukin 1alpha. A strong correlation between inhibition of aggrecan metabolism and inhibition of stromelysin 1 (MMP 3) (r=0.93) suggests a role for stromelysin or a stromelysin-like enzyme in cartilage aggrecan metabolism. However, the compounds were approx. 1/1000 as potent in inhibiting aggrecan loss from the cartilage explants as they were in inhibiting stromelysin. There was little or no correlation between inhibition of aggrecan metabolism and inhibition of gelatinase B (MMP 9) or inhibition of collagenase 1 (MMP 1). Studies with collagenase inhibitors with a range of potencies showed a correlation between inhibition of collagenase activity and inhibition of collagen degradation in the cartilage explant assay. This indicates that in interleukin 1alpha-driven bovine nasal cartilage destruction, stromelysin (or a closely related enzyme) is involved in aggrecan metabolism, whereas collagenase is principally responsible for collagen degradation.
authors.affiliation: Roche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Herts, AL7 3AY, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: Bottomley
authors.forename: N
authors.initials: N
authors.lastname: Borkakoti
authors.forename: D
authors.initials: D
authors.lastname: Bradshaw
authors.forename: P A
authors.initials: PA
authors.lastname: Brown
authors.forename: M J
authors.initials: MJ
authors.lastname: Broadhurst
authors.forename: J M
authors.initials: JM
authors.lastname: Budd
authors.forename: L
authors.initials: L
authors.lastname: Elliott
authors.forename: P
authors.initials: P
authors.lastname: Eyers
authors.forename: T J
authors.initials: TJ
authors.lastname: Hallam
authors.forename: B K
authors.initials: BK
authors.lastname: Handa
authors.forename: C H
authors.initials: CH
authors.lastname: Hill
authors.forename: M
authors.initials: M
authors.lastname: James
authors.forename: H W
authors.initials: HW
authors.lastname: Lahm
authors.forename: G
authors.initials: G
authors.lastname: Lawton
authors.forename: J E
authors.initials: JE
authors.lastname: Merritt
authors.forename: J S
authors.initials: JS
authors.lastname: Nixon
authors.forename: U
authors.initials: U
authors.lastname: Röthlisberger
authors.forename: A
authors.initials: A
authors.lastname: Whittle
authors.forename: W H
authors.initials: WH
authors.lastname: Johnson
mesh_terms: D053674:Aggrecans; D000818:Animals; D002417:Cattle; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type; D020781:Matrix Metalloproteinase 1; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009300:Nasal Septum / Q000378:metabolism*; D010449:Peptide Mapping; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D011508:Chondroitin Sulfate Proteoglycans; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D061965:Matrix Metalloproteinase Inhibitors; D011509:Proteoglycans; D003094:Collagen; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1