Relationships of matrix metalloproteinases and their inhibitors to cartilage proteoglycan and collagen turnover and inflammation as revealed by analyses of synovial fluids from patients with rheumatoid arthritis.
OBJECTIVE
To determine interrelationships in matrix turnover in articular cartilage and joint inflammation in rheumatoid arthritis (RA).


METHODS
Synovial fluid was obtained from the knees of 63 RA patients; radiographs were evaluated to determine the RA stage. Concentrations of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), the 846 epitope, and the keratan sulfate (KS) epitope of aggrecan, the C-propeptide of cartilage type II procollagen (CPII; biosynthetic marker), the cleavage of type II collagen by collagenase (CIIC; generated neoepitope), and polymorphonuclear leukocyte elastase (PMNE; inflammation marker) were measured by immunoassay. Concentrations of the unsaturated disaccharides of hyaluronic acid (delta di-HA) and the proteoglycan glycosaminoglycan disaccharides of chondroitins 4 and 6 sulfate (delta di-C4S and delta di-C6S) were determined by high-performance liquid chromatography.


RESULTS
MMP-3 was markedly increased in RA compared with osteoarthritis. Increases in TIMP-1 in RA were less pronounced and were inversely correlated with MMP-3 levels. CIIC was reduced in RA, as was the release of the KS epitope and delta di-C6S. In contrast, delta di-C4S and the 846 epitope were up-regulated. PMNE levels correlated with the 846 epitope and delta di-C4S, and more strongly with TIMPs 1 and 2. The changes may signify attempts at control of proteolysis in parallel with increased aggrecan turnover, which would favor matrix assembly. PMNE also correlated with MMP-9, and MMP-9 correlated with CPII. The delta di-HA level was decreased in RA and was inversely correlated with CPII and MMP-9 as well as with MMPs 2 and 3. In contrast, delta di-HA was directly correlated with TIMP-1 and the 846 epitope. These observations suggest that HA and PMNs may be involved in the control of proteolysis and cartilage proteoglycan assembly.


CONCLUSIONS
Our observations provide new insights into the complex changes in cartilage turnover and PMN influx in RA joints.
Ishiguro
N
N
Department of Orthopaedic Surgery, Nagoya University, School of Medicine, Japan. j46163a@nucc.cc.nagoya-u.ac.jp
Ito
T
T
Oguchi
T
T
Kojima
T
T
Iwata
H
H
Ionescu
M
M
Poole
A R
AR
D000328:Adult; D000368:Aged; D053674:Aggrecans; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000378:metabolism*; D003430:Cross-Sectional Studies; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D037181:Lectins, C-Type; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D011509:Proteoglycans / Q000378:metabolism*; D013582:Synovial Fluid / Q000378:metabolism; D013585:Synovitis / Q000378:metabolism* / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
D053674:Aggrecans; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans; D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D019272:Leukocyte Elastase; D020782:Matrix Metalloproteinases