TSG‐6 Is Weakly Chondroprotective in Murine OA but Does not Account for FGF2‐Mediated Joint Protection

Abstract

Objective. Tumor necrosis factor α-stimulated gene 6 (TSG-6) is an anti-inflammatory protein highly expressed in osteoarthritis (OA), but its influence on the course of OA is unknown. Methods. Cartilage injury was assessed by murine hip avulsion or by recutting rested explants. Forty-two previously validated injury genes were quantified by real-time polymerase chain reaction in whole joints following destabilization of the medial meniscus (DMM) (6 hours and 7 days). Joint pathology was assessed at 8 and 12 weeks following DMM in 10-week-old male and female fibroblast growth factor 2 (FGF2) −/− , TSG-6 −/− , TSG-6 tg (overexpressing), FGF2 −/− ;TSG-6 tg (8 weeks only) mice, as well as strain-matched, wild-type controls. In vivo cartilage repair was assessed 8 weeks following focal cartilage injury in TSG-6 tg and control mice. FGF2 release following cartilage injury was measured by enzyme-linked immunosorbent assay. Results. TSG-6 messenger RNA upregulation was strongly FGF2-dependent upon injury in vitro and in vivo. Fifteeen inflammatory genes were significantly increased in TSG-6 −/− joints, including IL1α, Ccl2, and Adamts5 compared with wild type. Six genes were significantly suppressed in TSG-6 −/− joints including Timp1, Inhibin βA, and podoplanin (known FGF2 target genes). FGF2 release upon cartilage injury was not influenced by levels of TSG-6. Cartilage degradation was significantly increased at 12 weeks post-DMM in male TSG-6 −/− mice, with a nonsignificant 30% reduction in disease seen in TSG-6 tg mice. No differences were observed in cartilage repair between genotypes. TSG-6 overexpression was unable to prevent accelerated OA in FGF2 −/− mice. Conclusion. TSG-6 influences early gene regulation in the destabilized joint and exerts a modest late chondroprotective effect. Although strongly FGF2 dependent, TSG-6 does not explain the strong chondroprotective effect of FGF2.

The recombinant Link module of human TSG-6 suppresses cartilage damage in models of osteoarthritis: a potential disease-modifying OA drug

“…However, our pellet culture and explant studies indicate that TSG-6 inhibits aggrecanse production and activity in experimental settings with high levels of inflammatory cytokines. This is consistent with a recent study showing that deletion of the Tsg6 gene in mice is associated with the rapid upregulation of proinflammatory and catabolic gene expression ( Adamts5, Ccl2 and Il1a ) following joint destabilisation[38]. Moreover, in human cartilage the level of ADAMTS5 protein is, in part, dictated by its residence time in the tissue, which is dependent on LRP-1-mediated endocytosis by chondrocytes[34]; in OA, uptake of ADAMTS5 is impaired via cytokine-dependent shedding of LRP-1 leading to increased aggrecanase activity[35].…”

“…Here we have shown that TSG-6 acts through a novel chondroprotective mechanism, suppressing inflammatory cytokine-mediated expression of the major aggrecanase and collagenase enzymes implicated in OA pathology. Thus, our observation that TSG-6 protein is largely associated with the most damaged regions of articular cartilage is consistent with it having an intrinsic function in tissue protection rather than driving the OA disease process [30,38]. Moreover, this aligns with a wealth of data on the reparative and anti-inflammatory effects of TSG-6 in a diverse range of animal models [22].…”

Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify cartilage damage in osteoarthritis

“…Whole knee joints were harvested as previously described, [32][33][34] and then homogenized using an adapted stainless steel mortar in liquid nitrogen. Tissue was lysed and protein quantified by Bradford method.…”

TSG-6 Inhibits the NF-κB Signaling Pathway and Promotes the Odontogenic Differentiation of Dental Pulp Stem Cells via CD44 in an Inflammatory Environment

“…In addition, TSG-6 affects mineralization-related diseases. The anti-inflammatory activity of TSG-6 is thought to underlie its cartilage-protective effects in rheumatoid arthritis (RA) models, and the application of TSG-6 protein or its overexpression significantly attenuates joint damage in RA models [ 20 , 21 ].…”