The regulation of MMPs and TIMPs in cartilage turnover.
The treatment of cartilage with mediators initiates the breakdown of proteoglycan followed by collagen. This is accompanied by the modulation of different proteinases and inhibitors that include members of the MMP family and TIMPs. We have evidence that a chondrocyte membrane-associated metalloproteinase cleaves aggrecan. This activity is rapidly induced after stimulation with IL-1 and OSM and is not inhibited by TIMPs-1 and -2 but is inhibited by synthetic MMP inhibitors. This same combination of cytokines also upregulates the collagenases with the subsequent release of collagen fragments, and there is a close correlation between the amount of collagen released and collagenase activity produced. Collagen release can be prevented after treatment with specific inhibitors of MAP kinases, inhibitors of MMP transcription, synthetic metalloproteinase inhibitors, TIMPs and treatment of cartilage with agents that upregulate TIMPs. The results from bovine cartilage culture models show that collagen release occurs when TIMP levels are low, collagenases are upregulated and then subsequently activated.
Department of Rheumatology, Medical School, University of Newcastle upon Tyne, England. T.E.Cawston@ncl.ac.uk
T
T
Cawston
C
C
Billington
C
C
Cleaver
S
S
Elliott
W
W
Hui
P
P
Koshy
B
B
Shingleton
A
A
Rowan
D053674:Aggrecans; D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003470:Culture Media; D016207:Cytokines / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology; D016326:Extracellular Matrix Proteins; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007403:Intervertebral Disc / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D037181:Lectins, C-Type; D008666:Metalloendopeptidases / Q000378:metabolism*; D009300:Nasal Septum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
D053674:Aggrecans; D003470:Culture Media; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D007375:Interleukin-1; D037181:Lectins, C-Type; C508351:OSM protein, human; D010455:Peptides; D011509:Proteoglycans; D019714:Tissue Inhibitor of Metalloproteinases; D053683:Oncostatin M; D015847:Interleukin-4; D010450:Endopeptidases; D008666:Metalloendopeptidases; C083641:aggrecanase