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a Musculoskeletal
Research Group, Stopford Building, University of Manchester, Manchester
M13 9PT, b Procter and Gamble Pharmaceuticals, Cincinnati,
Ohio, USA
Correspondence to: Professor A J Freemont.
Accepted for publication 5 February 1999
OBJECTIVES
Chondrocytic
matrix metalloproteinases (MMPs) are believed to be important in
osteoarthritic cartilage degradation. The cartilage lesion of
osteoarthritis (OA) is focal and often progressive. During its
development chondrocytes differentially up and down regulate production
of mRNA for individual MMPs. This observation has potential
implications for understanding the disease processes that lead to
progressive cartilage loss in OA and designing appropriate targeted
treatment. The complex regulation of MMP mediated effects means there
is a pressing need to establish whether visualisation of MMP mRNA or
protein equates to enzyme activity. The technique of in situ zymography
(ISZ) offers a way of examining diseased human tissue for in vivo
production of an excess of degrading enzyme over inhibitor. The primary
objective of this study was to assess, and if positive follow, collagen
II degrading activity in cartilage during development of the OA
lesion. A secondary objective was to assess whether there was any
correlation between sites of collagen II degrading activity and
expression of the collagenase (MMP-13), recently implicated in type II
collagen degredation in this lesion.
METHODSBiopsied
human normal and osteoarthritic cartilage, showing various degrees of
damage, was examined by in situ zymography, with and without enzyme
inhibitors, to establish sites of type II collagenase activity. Paired
samples were probed for MMP-13 mRNA using 35S-labelled
oligonucleotide probes. Comparative analyses were performed.
RESULTSIn situ
zymography showed collagen II degrading activity over chondrocytes only
in osteoarthritic cartilage. Distribution and amount varied with the
extent of cartilage damage and position of chondrocytes, being greatest
in deep cartilage and in cartilage lesions where fissuring was
occurring. The enzyme causing the degradation behaved as a matrix
metalloproteinase. MMP-13 mRNA expression codistributed with the type
II collagenase activity.
CONCLUSIONIn OA,
chondrocytes can degrade type II collagen. The type II collagen
degrading activity varies in site and amount as the cartilage lesion
progresses and throughout codistributes with MMP-13 mRNA expression.
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