TNF alpha-stimulated gene 6 (TSG6) is chondroprotective in vivo but overexpression cannot compensate for loss of FGF2

Abstract

Purpose: TNF alpha stimulated gene 6 (TSG6) is expressed in response to tissue injury and has purported tissue-protective and anti-inflammatory effects. High levels of TSG6 have been detected in the synovial fluid of patients with OA and following acute knee injury. Our published work shows that TSG6 is regulated after joint destabilisation in mice, in a highly mechanosensitive and fibroblast growth factor 2 (FGF2)-dependent fashion. As FGF2-/- mice develop accelerated OA, and injury-induced FGF2-dependent genes such as Timp1 and inhibin were downregulated in TSG-6-/- mouse joints, we speculated that the chondroprotective role of FGF2 may be mediated through TSG6. We asked whether overexpressing TSG-6 could reduce the severity of OA in wild type or FGF2-/- mice. Methods: OA was induced by cutting the medial menisco-tibial ligament (DMM) in 10-12 week old male and female TSG6-/-, TSG6tg, FGF2-/- mice with their respective controls (C57BL/6 and Balb/c), and male FGF2-/-;TSG6tg+/+ or FGF2-/-;TSG6tg-/- mice. Focal cartilage injury was also performed in male and female TSG6tg mice. 8 and 12 weeks post-surgery, joints were sectioned and the severity of cartilage degradation was assessed according to a modified OARSI score. FGF2 levels were measured in cartilage injury conditioned medium from FGF2-/-, Balb/c, TSG-6tg+/+, TSG-6tg-/+, TSG-6tg-/- hips by V-PLEX bFGF kit from Meso Scale Discovery (MSD, Rockville, MD). Results: Accelerated OA was seen in TSG6-/- male mice at 12 but not 8 weeks post DMM compared with wild type (C57BL/6). A reciprocal improvement in OA scores was seen in male TSG6Tg mice 12 weeks after DMM. FGF2−/− mice developed accelerated OA post DMM as shown previously, but overexpression of TSG6 (FGF2-/-;TSG6tg+/+) was unable to overcome this. There was no significant difference observed in cartilage repair scores 8 weeks after focal cartilage injury in male or female TSG-6tg mice compared with wild type (Balb/c). Secreted FGF2 in cartilage injury conditioned medium was not influenced by genotype indicating that the bioavailability of FGF2 is not determined by TSG-6. Conclusions: TSG-6 is weakly chondroprotective in murine OA. Despite being strongly FGF2 dependent in vivo, TSG6 overexpression does not protect FGF2-/- mice from accelerated OA. The chondroprotective role of FGF2 cannot be explained by FGF2-dependent regulation of TSG6.