Antisense oligonucleotides, a novel tool for the control of cytokine effects on human cartilage. Focus on interleukins 1 and 6 and proteoglycan synthesis.
OBJECTIVE
To prevent the negative effects of interleukin-1 (IL-1) and IL-1-induced IL-6 on cartilage proteoglycan (PG) synthesis, we used an antisense oligonucleotide (ASO) specific for IL-6 messenger RNA (mRNA) to inhibit IL-6 production.


METHODS
Explants of human articular cartilage were cultured in the presence or absence of IL-6-ASO, IL-1, and exogenous IL-6. As metabolic parameters, cartilage production of IL-6 was determined in the B9 bioassay and PG as incorporation of 35SO4.


RESULTS
The IL-6-ASO prevented IL-1-induced production of IL-6 in the cartilage explants, as well as IL-1-induced inhibition of PG synthesis. This inhibition was restored, despite the presence of IL-6-ASO, when exogenous IL-6 was added. A control ASO (not specific for IL-6 mRNA) was not effective.


CONCLUSIONS
The IL-6-ASO used can penetrate the extracellular matrix of articular cartilage, enter the chondrocytes, and inhibit the IL-1-induced production of IL-6. Furthermore, IL-6-ASO can prevent the IL-1-induced inhibition of cartilage PG synthesis. The effect of exogenous IL-6 shows that IL-1 requires IL-6 for inhibition of PG synthesis.
Nietfeld
J J
JJ
University Hospital, Utrecht, The Netherlands.
Duits
A J
AJ
Tilanus
M G
MG
van den Bosch
M E
ME
Den Otter
W
W
Capel
P J
PJ
Bijlsma
J W
JW
D000368:Aged; D001681:Biological Assay; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology*; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009994:Osmolar Concentration; D011509:Proteoglycans / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; D012333:RNA, Messenger; D000093242:Interleukin-6 Inhibitors