Osteopontin - An intrinsic inhibitor of inflammation in cartilage

Objective. To identify extracellular and intraarticular matrix components that are differentially expressed in normal and osteoarthritis (OA)-affected cartilage and to investigate their functions with respect to regulation of mediators of inflammation. Methods. Differential-display reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of a pool of messenger RNA (mRNA) from 10 human OA cartilage samples and 5 normal cartilage samples was performed using arbitrary primers. Confirmatory analysis of the up-regulated transcripts of fibronectin (FN) and osteopontin (OPN) was performed by RT-PCR of individual RNA samples from a separate set of donors. The effect of recombinant OPN (or anti-OPN antiserum) on chondrocyte function was examined by analyzing the spontaneous or interleukin-1 (IL-1)-induced release of nitric oxide (NO) and prostaglandin E-2 (PGE(2)) from human OA-affected cartilage under ex vivo conditions. Results. Up-regulation (300-700%) of FN and OPN mRNA was observed in human OA-affected cartilage as compared with normal cartilage. Functional analysis of the role of OPN in OA cartilage showed that 1) Addition of 1 mu /ml (20 nM) of recombinant OPN to human OA-affected cartilage under ex vivo conditions inhibited spontaneous and IL-1 beta -induced NO and PGE(2) production, and 2) neutralization of intraarticular OPN with anti-OPN antiserum augmented NO production. Conclusion. The data indicate that one of the functions of intraarticular OPN, which is overexpressed in OA cartilage, is to act as an innate inhibitor of IL-1, NO, and PGE(2) production. These findings suggest that the production of pleiotropic mediators of inflammation that influence cartilage homeostasis, such as NO and PGE(2), is regulated by the interaction of chondrocytes with differentially expressed proteins within the extracellular matrix.