The majority of cytokines and growth factors known to be involved in cartilage metabolism are synthesized by the chondrocytes themselves. They are up-regulated in osteoarthritic (OA) cartilage, resulting in 2 opposite phenotypes, TNFalpha(high) and TNFalpha(low), that are characterized by an elevated number of tumor necrosis factor alpha (TNFalpha)-positive and interleukin-1beta (IL-1beta)-positive chondrocytes, respectively. To establish a hierarchy among the cytokines and growth factors expressed in articular chondrocytes, this study investigated cytokine genes for known polymorphisms that may contribute to the deregulated expression in OA cartilage.
Polymerase chain reaction techniques were performed either in a thermal cycler using standard methods or in a light cycler to analyze the frequencies of the TNFalpha (-308), IL-1 receptor antagonist (IL-1Ra) (intron 2), IL-1beta (exon 5), and IL-6 (-174) polymorphisms in 61 OA patients and 254 randomly chosen controls.
For the TNFalpha(low) phenotype, a statistically significant association was found with the less frequent allele of IL-1beta, which carries a single-basepair substitution in exon 5 and may contribute to the characteristic increase in IL-beta-positive chondrocytes. In contrast, the TNFalpha(high) phenotype was significantly associated with the less frequent allele of IL-1Ra, which carries two 86-bp repeats in the second intron and is assumed to lead to an elevated expression of the antagonist.
These results point to an association between the IL-1beta polymorphism and the TNFalpha(high) phenotype and between the IL-1Ra polymorphism and the TNFalpha(low) phenotype found in OA. Both associations suggest that IL-1beta may be more important than TNFalpha for the regulation of cytokine and growth factor expression in articular chondrocytes.