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Biochem J. Apr 15, 1997; 323(Pt 2): 483–488.
PMCID: PMC1218345

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.

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Selected References

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  • Krane SM. IV. Joint erosion in rheumatoid arthritis. Arthritis Rheum. 1974 May-Jun;17(3):306–312. [PubMed]
  • Fosang AJ, Last K, Knäuper V, Neame PJ, Murphy G, Hardingham TE, Tschesche H, Hamilton JA. Fibroblast and neutrophil collagenases cleave at two sites in the cartilage aggrecan interglobular domain. Biochem J. 1993 Oct 1;295(Pt 1):273–276. [PMC free article] [PubMed]
  • Nixon JS, Bottomley KM, Broadhurst MJ, Brown PA, Johnson WH, Lawton G, Marley J, Sedgwick AD, Wilkinson SE. Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro. Int J Tissue React. 1991;13(5):237–241. [PubMed]
  • Caputo CB, Sygowski LA, Wolanin DJ, Patton SP, Caccese RG, Shaw A, Roberts RA, DiPasquale G. Effect of synthetic metalloprotease inhibitors on cartilage autolysis in vitro. J Pharmacol Exp Ther. 1987 Feb;240(2):460–465. [PubMed]
  • Seed MP, Thomson TA, Gardner CR. Investigation of the role of metalloproteinases in recombinant human interleukin-1 beta-induced degradation of rat femoral head cartilage. Drugs Exp Clin Res. 1991;17(7):355–361. [PubMed]
  • Cawston T, Plumpton T, Curry V, Ellis A, Powell L. Role of TIMP and MMP inhibition in preventing connective tissue breakdown. Ann N Y Acad Sci. 1994 Sep 6;732:75–83. [PubMed]
  • Ratcliffe A, Tyler JA, Hardingham TE. Articular cartilage cultured with interleukin 1. Increased release of link protein, hyaluronate-binding region and other proteoglycan fragments. Biochem J. 1986 Sep 1;238(2):571–580. [PMC free article] [PubMed]
  • Couchman JR, Caterson B, Christner JE, Baker JR. Mapping by monoclonal antibody detection of glycosaminoglycans in connective tissues. Nature. 1984 Feb 16;307(5952):650–652. [PubMed]
  • Lohmander LS, Neame PJ, Sandy JD. The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis. Arthritis Rheum. 1993 Sep;36(9):1214–1222. [PubMed]
  • Sandy JD, Flannery CR, Neame PJ, Lohmander LS. The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain. J Clin Invest. 1992 May;89(5):1512–1516. [PMC free article] [PubMed]
  • Lark MW, Gordy JT, Weidner JR, Ayala J, Kimura JH, Williams HR, Mumford RA, Flannery CR, Carlson SS, Iwata M, et al. Cell-mediated catabolism of aggrecan. Evidence that cleavage at the "aggrecanase" site (Glu373-Ala374) is a primary event in proteolysis of the interglobular domain. J Biol Chem. 1995 Feb 10;270(6):2550–2556. [PubMed]
  • Wertheimer S, Katz S, Rowan K, Lugo A, Levin W, Hanglow AC. Stromelysin expression in IL-1 beta stimulated bovine articular cartilage explants. Inflamm Res. 1995 Aug;44 (Suppl 2):S119–S120. [PubMed]
  • Gubler U, Chua AO, Stern AS, Hellmann CP, Vitek MP, DeChiara TM, Benjamin WR, Collier KJ, Dukovich M, Familletti PC, et al. Recombinant human interleukin 1 alpha: purification and biological characterization. J Immunol. 1986 Apr 1;136(7):2492–2497. [PubMed]
  • Johnson-Wint B. A quantitative collagen film collagenase assay for large numbers of samples. Anal Biochem. 1980 May 1;104(1):175–181. [PubMed]
  • Ito A, Nagase H. Evidence that human rheumatoid synovial matrix metalloproteinase 3 is an endogenous activator of procollagenase. Arch Biochem Biophys. 1988 Nov 15;267(1):211–216. [PubMed]
  • Ward RV, Hembry RM, Reynolds JJ, Murphy G. The purification of tissue inhibitor of metalloproteinases-2 from its 72 kDa progelatinase complex. Demonstration of the biochemical similarities of tissue inhibitor of metalloproteinases-2 and tissue inhibitor of metalloproteinases-1. Biochem J. 1991 Aug 15;278(Pt 1):179–187. [PMC free article] [PubMed]
  • Farndale RW, Buttle DJ, Barrett AJ. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta. 1986 Sep 4;883(2):173–177. [PubMed]
  • Ho KC, Pang CP. Automated analysis of urinary hydroxyproline. Clin Chim Acta. 1989 Nov;185(2):191–195. [PubMed]
  • Hewick RM, Hunkapiller MW, Hood LE, Dreyer WJ. A gas-liquid solid phase peptide and protein sequenator. J Biol Chem. 1981 Aug 10;256(15):7990–7997. [PubMed]
  • Sandy JD, Neame PJ, Boynton RE, Flannery CR. Catabolism of aggrecan in cartilage explants. Identification of a major cleavage site within the interglobular domain. J Biol Chem. 1991 May 15;266(14):8683–8685. [PubMed]
  • Loulakis P, Shrikhande A, Davis G, Maniglia CA. N-terminal sequence of proteoglycan fragments isolated from medium of interleukin-1-treated articular-cartilage cultures. Putative site(s) of enzymic cleavage. Biochem J. 1992 Jun 1;284(Pt 2):589–593. [PMC free article] [PubMed]
  • Fosang AJ, Neame PJ, Hardingham TE, Murphy G, Hamilton JA. Cleavage of cartilage proteoglycan between G1 and G2 domains by stromelysins. J Biol Chem. 1991 Aug 25;266(24):15579–15582. [PubMed]
  • Flannery CR, Lark MW, Sandy JD. Identification of a stromelysin cleavage site within the interglobular domain of human aggrecan. Evidence for proteolysis at this site in vivo in human articular cartilage. J Biol Chem. 1992 Jan 15;267(2):1008–1014. [PubMed]
  • Fosang AJ, Last K, Neame PJ, Murphy G, Knäuper V, Tschesche H, Hughes CE, Caterson B, Hardingham TE. Neutrophil collagenase (MMP-8) cleaves at the aggrecanase site E373-A374 in the interglobular domain of cartilage aggrecan. Biochem J. 1994 Dec 1;304(Pt 2):347–351. [PMC free article] [PubMed]
  • Knäuper V, López-Otin C, Smith B, Knight G, Murphy G. Biochemical characterization of human collagenase-3. J Biol Chem. 1996 Jan 19;271(3):1544–1550. [PubMed]
  • Mitchell PG, Lopresti-Morrow L, Yocum SA, Sweeney FJ, Reiter LA. Inhibition of interleukin-1-stimulated collagen degradation in cartilage explants. Ann N Y Acad Sci. 1994 Sep 6;732:395–397. [PubMed]
  • Cole AA, Chubinskaya S, Schumacher B, Huch K, Szabo G, Yao J, Mikecz K, Hasty KA, Kuettner KE. Chondrocyte matrix metalloproteinase-8. Human articular chondrocytes express neutrophil collagenase. J Biol Chem. 1996 May 3;271(18):11023–11026. [PubMed]
  • Pettipher ER, Higgs GA, Henderson B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8749–8753. [PMC free article] [PubMed]
  • Fell HB, Barratt ME, Welland H, Green R. The capacity of pig articular cartilage in organ culture to regenerate after breakdown induced by complement-sufficient antiserum to pig erythrocytes. Calcif Tissue Res. 1976 Apr 13;20(1):3–21. [PubMed]

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