title: Cartilage degradation independent of MMP/aggrecanases.
abstract: OBJECTIVE
  To identify and characterize a cartilage degradation mechanism that is independent of the proteolytic cleavages by matrix metalloproteinases (MMPs) and aggrecanases.
  
  
  METHODS
  The sensitivity of glycosaminoglycan (GAG) release and collagen release to an MMP/aggrecanase inhibitor, AG3340, was compared using a bovine nasal cartilage explant culture. The release of matrix proteins and hyaluronan (HA) from the culture was analyzed by immunoblotting and radioimmunoassay, respectively. Induction of HA-degrading activity by retinoic acid was examined using the cartilage explant culture and a primary culture of chondrocytes. Degradation of the matrix components of cartilage was also characterized in vivo using an acute arthritis model induced by an intra-articular injection of interleukin 1alpha (IL-1alpha).
  
  
  RESULTS
  AG3340 did not effectively inhibit GAG release at a concentration of more than 10muM, while 10nM of the inhibitor completely suppressed collagen degradation. Retinoic acid induced the release of the aggrecan G1 domain, link protein and HA into the culture medium, and the release of these molecules was not completely inhibited by 10muM of AG3340. The molecules were released as ternary complexes. Retinoic acid induced HA degradation in the explant culture and hyaluronidase activity in the primary culture of chondrocytes. The release of the G1 domain of aggrecan and link protein into the synovial fluid was also observed in the IL-1alpha-induced acute arthritis model.
  
  
  CONCLUSIONS
  A novel mechanism by chondrocyte-derived hyaluronidase(s) is involved in the release of the matrix components from cartilage, and the hyaluronidase(s) and MMPs/aggrecanases act in a coordinated manner in cartilage degradation.
authors.affiliation: Lead Discovery Research Laboratories, Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Iizawa
authors.forename: Hosami
authors.initials: H
authors.lastname: Harada
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamada
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Katsumata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D053674:Aggrecans; D000818:Animals; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002417:Cattle; D024043:Collagen Type II / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type; D061965:Matrix Metalloproteinase Inhibitors; D053683:Oncostatin M; D009930:Organic Chemicals / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D011817:Rabbits; D013268:Stimulation, Chemical; D013582:Synovial Fluid / Q000737:chemistry; D046509:Tissue Culture Techniques; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D053674:Aggrecans; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D007375:Interleukin-1; D037181:Lectins, C-Type; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010455:Peptides; D011509:Proteoglycans; D053683:Oncostatin M; C113282:prinomastat; D014212:Tretinoin; D010450:Endopeptidases; C083641:aggrecanase