Inhibition of cartilage proteoglycan release by a specific inactivator of cathepsin B and an inhibitor of matrix metalloproteinases. Evidence for two converging pathways of chondrocyte-mediated proteoglycan degradation

Arthritis Rheum. 1993 Dec;36(12):1709-17. doi: 10.1002/art.1780361210.

Abstract

Objective: To investigate mechanisms of cartilage matrix destruction by a study of the effects of a specific inactivator of cathepsin B and an inhibitor of several matrix metalloproteinases (MMP) on cartilage proteoglycan release.

Methods: Cartilage explants were treated with either recombinant human interleukin-1 alpha (rHuIL-1 alpha) or retinoic acid in the presence or absence of the inhibitors, and proteoglycan release was quantitated. Tests for nonspecific effects of the inhibitors included reversibility, rates of protein synthesis and glycolysis, and effects on other rHuIL-1 alpha-mediated events.

Results: The cathepsin B inactivator inhibited rHuIL-1 alpha-stimulated proteoglycan release at nanomolar concentrations, but failed to significantly inhibit retinoic acid-stimulated proteoglycan release. An inhibitor of MMP was inhibitory to both rHuIL-1 alpha-stimulated release and retinoic acid-stimulated release.

Conclusion: Cathepsin B is implicated in rHuIL-1 alpha-stimulated loss of cartilage proteoglycan. Its lack of involvement in retinoic acid-stimulated proteoglycan release suggests the existence of at least 2 pathways of cartilage proteoglycan breakdown, which may converge at the activation of a matrix prometalloproteinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggrecans
  • Amino Acid Sequence
  • Animals
  • Cartilage / chemistry*
  • Cartilage / enzymology
  • Cartilage, Articular / enzymology
  • Cathepsin B / antagonists & inhibitors*
  • Cattle
  • Dipeptides / pharmacology
  • Enzyme Activation
  • Extracellular Matrix Proteins*
  • Interleukin-1 / pharmacology
  • Lectins, C-Type
  • Metalloendopeptidases / antagonists & inhibitors*
  • Molecular Sequence Data
  • Nasal Septum / chemistry
  • Nasal Septum / drug effects
  • Nasal Septum / metabolism
  • Peptide Fragments / chemistry
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology
  • Proteoglycans / chemistry
  • Proteoglycans / drug effects
  • Proteoglycans / metabolism*
  • Recombinant Proteins / pharmacology
  • Thiophenes / pharmacology
  • Tretinoin / pharmacology

Substances

  • Aggrecans
  • Dipeptides
  • Extracellular Matrix Proteins
  • Interleukin-1
  • Lectins, C-Type
  • Peptide Fragments
  • Proteoglycans
  • Recombinant Proteins
  • Thiophenes
  • N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline
  • Phenylalanine
  • Tretinoin
  • batimastat
  • Cathepsin B
  • Metalloendopeptidases