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. Conclusion. 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.