Effects of interferon-γ and tumor necrosis factor α on the expression of the genes encoding aggrecan, biglycan, and decorin core proteins in cultured human chondrocytes

Objective To determine the effects of interferon-γ (IFNγ) and tumor necrosis factor α (TNFα), alone or in combination, on the expression of aggrecan, biglycan, and decorin core protein genes in human chondrocytes. Methods Isolated human chondrocytes were cultured on poly(2-hydroxyethyl methacrylate)-coated plastic dishes to prevent the loss of cartilage-specific phenotype, and the effects of IFNγ and TNFα, alone or in combination, on aggrecan, biglycan, and decorin core protein gene transcription and steady-state messenger RNA (mRNA) levels were examined. Results The addition of IFNγ (1.5 pM) or TNFα (0.3 pM) caused a decrease in the steady-state level of aggrecan mRNA (-25% and -15%, respectively), and the combination of these low-concentration cytokines caused a potent inhibition (-66%). These effects were the result of a decrease (-50%) in the transcription rate of the corresponding gene. At the concentrations used, IFNγ did not alter the levels of biglycan mRNA or the transcription rates of the biglycan core protein gene. In contrast, TNFα decreased biglycan steady-state mRNA levels (-62%) and the biglycan core protein gene transcription rate (-18%). The combination of IFNγ and TNFα resulted in a potentiation of the inhibitory effects of TNFα on biglycan mRNA levels (-79%) and transcription rate of the biglycan core protein gene (-46%). IFNγ produced a modest decrease in decorin mRNA levels (-23%) and decorin core protein gene transcription rate (-17%). In contrast, TNFα resulted in a marked increase in decorin mRNA levels (+260%) that was not the result of transcriptional regulation. Notably, the combination of IFNγ and TNFα potentiated the inhibitory effects of IFNγ on decorin mRNA (-80%) and on the transcription of the corresponding gene (-43%). Similar results were obtained in fetal and adult articular chondrocytes. Conclusion These data demonstrate that 1) the expression of the core protein genes encoding the cartilage proteoglycans aggrecan, biglycan, and decorin is differentially regulated by IFNγ and TNFα; 2) these effects are mediated by transcriptional and posttranscriptional mechanisms; and 3) the combination of the 2 cytokines causes a potent inhibitory effect on the expression of the genes for the core proteins of these 3 proteoglycans, which occurs largely at the transcriptional level. The inhibition of aggrecan, decorin, and biglycan core protein gene expression by the combination of IFNγ and TNFα may contribute to the cartilage destruction that is characteristic of inflammatory joint diseases.