PMID- 11592371
OWN - NLM
STAT- MEDLINE
DCOM- 20011101
LR  - 20141120
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 44
IP  - 9
DP  - 2001 Sep
TI  - Activation of procollagenases is a key control point in cartilage collagen 
      degradation: interaction of serine and metalloproteinase pathways.
PG  - 2084-96
AB  - OBJECTIVE: Bovine and human cartilages in explant culture respond to 
      proinflammatory cytokines with the up-regulation of procollagenases. In 
      stimulated bovine nasal cartilage (BNC), >90% of collagen is released by day 14 
      of culture, but collagen release is rarely seen before day 7. The aim of this 
      study was to investigate if activation of procollagenases is a rate-limiting step 
      in cartilage collagen breakdown. METHODS: BNC and human articular cartilage 
      explants were cultured with interleukin-1alpha (IL-1alpha) and/or oncostatin M 
      (OSM) with or without test reagents. Collagen levels were determined by assay of 
      hydroxyproline. Collagenase activity was measured using the diffuse fibril assay. 
      RESULTS: The addition of procollagenase activators, matrix metalloproteinase 3 
      (MMP-3), and APMA to IL-1alpha/OSM-stimulated BNC resulted in early release of 
      collagen. The release with APMA was completely blocked by the addition of tissue 
      inhibitor of metalloproteinases 1. This shows that procollagenases are present 
      early in the culture period, but cartilage collagen breakdown does not happen 
      until activation occurs. The addition of plasminogen to IL-1alpha/OSM-stimulated 
      cartilage produced early collagen release in bovine and a significant increase in 
      human cartilage. Thus, plasminogen activators (PAs) are present and convert 
      plasminogen to plasmin, a known activator of several MMPs, including 
      collagenases. Addition of alpha1-proteinase inhibitor or a urokinase-type PA 
      inhibitor, 7-amino-4-chloro-3-(3-isothiureidopropoxy) isocoumarin, partially 
      blocked the breakdown of collagen from IL-1alpha/OSM-treated bovine cartilage. 
      This suggests that serine proteinases are involved in the activation cascades of 
      procollagenases that result in cartilage collagen breakdown. CONCLUSION: The 
      activation of procollagenases is a key control point in cartilage collagen 
      breakdown, and serine proteinase pathways activate MMPs.
FAU - Milner, J M
AU  - Milner JM
AD  - Department of Rheumatology, The Medical School, University of 
      Newcastle-upon-Tyne, England, UK.
FAU - Elliott, S F
AU  - Elliott SF
FAU - Cawston, T E
AU  - Cawston TE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Enzyme Precursors)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Growth Inhibitors)
RN  - 0 (Interleukin-1)
RN  - 0 (OSM protein, human)
RN  - 0 (Peptides)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Thiophenes)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 106956-32-5 (Oncostatin M)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - 9001-91-6 (Plasminogen)
RN  - 9007-34-5 (Collagen)
RN  - BK349F52C9 (batimastat)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - EC 3.4.24.- (Collagenases)
RN  - EC 3.4.24.- (procollagenase)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Animals
MH  - Cartilage, Articular/*cytology/*enzymology
MH  - Cattle
MH  - Cells, Cultured
MH  - Collagen/*metabolism
MH  - Collagenases/*metabolism
MH  - Enzyme Activation/drug effects/physiology
MH  - Enzyme Precursors/*metabolism
MH  - Fibrinolytic Agents/pharmacology
MH  - Growth Inhibitors/pharmacology
MH  - Humans
MH  - Interleukin-1/pharmacology
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Oncostatin M
MH  - Peptides/pharmacology
MH  - Phenylalanine/analogs & derivatives/pharmacology
MH  - Plasminogen/pharmacology
MH  - Protease Inhibitors/pharmacology
MH  - Serine Endopeptidases/*metabolism
MH  - Thiophenes/pharmacology
MH  - Tissue Inhibitor of Metalloproteinase-1/pharmacology
EDAT- 2001/10/11 10:00
MHDA- 2001/11/03 10:01
CRDT- 2001/10/11 10:00
PHST- 2001/10/11 10:00 [pubmed]
PHST- 2001/11/03 10:01 [medline]
PHST- 2001/10/11 10:00 [entrez]
AID - 10.1002/1529-0131(200109)44:9<2084::AID-ART359>3.0.CO;2-R [doi]
PST - ppublish
SO  - Arthritis Rheum. 2001 Sep;44(9):2084-96. doi: 
      10.1002/1529-0131(200109)44:9<2084::AID-ART359>3.0.CO;2-R.