Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis.
OBJECTIVE
Despite many research efforts in recent decades, the major pathogenetic mechanisms of osteoarthritis (OA), including gene alterations occurring during OA cartilage degeneration, are poorly understood, and there is no disease-modifying treatment approach. The present study was therefore initiated in order to identify differentially expressed disease-related genes and potential therapeutic targets.


METHODS
This investigation consisted of a large gene expression profiling study performed based on 78 normal and disease samples, using a custom-made complementary DNA array covering >4,000 genes.


RESULTS
Many differentially expressed genes were identified, including the expected up-regulation of anabolic and catabolic matrix genes. In particular, the down-regulation of important oxidative defense genes, i.e., the genes for superoxide dismutases 2 and 3 and glutathione peroxidase 3, was prominent. This indicates that continuous oxidative stress to the cells and the matrix is one major underlying pathogenetic mechanism in OA. Also, genes that are involved in the phenotypic stability of cells, a feature that is greatly reduced in OA cartilage, appeared to be suppressed.


CONCLUSIONS
Our findings provide a reference data set on gene alterations in OA cartilage and, importantly, indicate major mechanisms underlying central cell biologic alterations that occur during the OA disease process. These results identify molecular targets that can be further investigated in the search for therapeutic interventions.
Aigner
Thomas
T
Osteoarticular and Arthritis Research, Institute of Pathology, University of Leipzig, Liebigstrasse 26, D-04103 Leipzig, Germany. thomas.aigner@medizin.uni-leipzig.de
Fundel
Katrin
K
Saas
Joachim
J
Gebhard
Pia M
PM
Haag
Jochen
J
Weiss
Tilo
T
Zien
Alexander
A
Obermayr
Franz
F
Zimmer
Ralf
R
Bartnik
Eckart
E
D000368:Aged; D000369:Aged, 80 and over; D002356:Cartilage / Q000473:pathology*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D016172:DNA Fingerprinting; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods* / Q000592:standards; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D015203:Reproducibility of Results; D012720:Severity of Illness Index
D005819:Genetic Markers