Interleukin-1 in combination with oncostatin M up-regulates multiple genes in chondrocytes: implications for cartilage destruction and repair.
OBJECTIVE
To identify the genes up-regulated by interleukin-1 (IL-1) in combination with oncostatin M (OSM) in chondrocytes that may be involved in mechanisms of cartilage repair and degradation.


METHODS
Gene microarray and real-time polymerase chain reaction (PCR) experiments were performed using RNA from SW1353 chondrocytes and primary human articular chondrocytes. Sections prepared from murine joints, injected with adenovirus vectors overexpressing IL-1 and/or OSM, were analyzed by immunohistochemistry for selected proteins.


RESULTS
The combination of IL-1 and OSM markedly up-regulated the expression of various genes, including matrix metalloproteinases (MMPs), cytokines, chemokines, extracellular matrix components, and genes involved in signal transduction. Real-time PCR confirmed a synergistic induction of several MMPs, activin A, pentraxin 3 (PTX-3), and IL-8. The in vivo findings further indicated that stimulation with IL-1 plus OSM induced protein expression of activin A, PTX-3, and KC (the murine homolog of IL-8), as compared with the changes induced by individual cytokine treatment and unstimulated controls.


CONCLUSIONS
The results confirm that the potent proinflammatory cytokine combination of IL-1 plus OSM synergistically and coordinately up-regulates many genes and several MMPs. Moreover, chondrocytes exhibit a potential repair response following this procatabolic stimulus such that the repair mechanisms are ultimately overwhelmed by degradative processes in the cartilage. This gene-profiling study provides insight into the complex processes that mediate joint disease in the inflammatory arthritides through the coordinated expression of multiple genes.
Barksby
H E
HE
University of Newcastle, Newcastle upon Tyne, UK.
Hui
W
W
Wappler
I
I
Peters
H H
HH
Milner
J M
JM
Richards
C D
CD
Cawston
T E
TE
Rowan
A D
AD
D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000473:pathology; D020219:Chondrogenesis / Q000187:drug effects* / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D053683:Oncostatin M; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
D016207:Cytokines; D004338:Drug Combinations; D018836:Inflammation Mediators; D007375:Interleukin-1; C508351:OSM protein, human; D012333:RNA, Messenger; D053683:Oncostatin M