TWEAK and Fn14 expression in osteoarthritis: evidence for TWEAK-induced RANKL release from chondrocytes

ObjectiveA role for TWEAK expression and that of its receptor Fn14 by osteoblasts and synovial tissue has been proposed in the pathogenesis of osteoarthritis (OA). Here, we examined whether the cartilage in OA was also a source and target of TWEAK. DesignArticular cartilage samples from 24 patients undergoing hip or knee replacement surgery for OA were investigated for TWEAK and Fn14 expression by both immunostaining and real-time RT-PCR. Human primary chondrocytes isolated from OA cartilage were treated with combinations of recombinant TWEAK and TNF and examined for the regulation of TWEAK, FN14, RANKL, ADAM17 and SOST mRNA levels. Soluble RANKL levels were measured by ELISA. ResultsTWEAK and Fn14 mRNA levels were elevated in grade 2 OA cartilage compared to grade 0 (p < 0.05). Immunostaining indicated that the majority (21/24) of OA cartilage samples expressed low levels of TWEAK protein and high levels of Fn14, however, expression did not appear to vary with respect to OA grade. Primary chondrocytes treated with TNF exhibited upregulated TWEAK and Fn14 mRNA expression. SOST mRNA expression was inhibited by both TWEAK and TNF treatment. TWEAK transiently induced RANKL mRNA expression while both TWEAK and TNF induced sRANKL release by chondrocytes. TWEAK and TNF also induced the mRNA expression of the RANKL sheddase, ADAM17. ConclusionsTWEAK and Fn14 mRNA expression is elevated in OA articular cartilage. The TWEAK and TNF induction of ADAM17 expression and sRANKL released by chondrocytes in vitro, as well as suppression of sclerostin/SOST, points to a potential catabolic role for these mediators in OA.