Abstract
ObjectiveTumor 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.MethodsCartilage 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‐6tg (overexpressing), FGF2−/−;TSG‐6tg (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‐6tg and control mice. FGF2 release following cartilage injury was measured by enzyme‐linked immunosorbent assay.ResultsTSG‐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‐6tg mice. No differences were observed in cartilage repair between genotypes. TSG‐6 overexpression was unable to prevent accelerated OA in FGF2−/− mice.ConclusionTSG‐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.
Highlights
Tumor necrosis factor alpha (TNF-α) stimulated gene 6 (TSG-6) is a secreted product of TNF-α–treated cells [1], which encodes for a 35 kDa multifunctional protein, consisting of Link and CUB modules [2,3,4]
TSG-6 was strongly induced upon recutting injury or fibroblast growth factor 2 (FGF2) stimulation (Figure 2A). It was strongly upregulated in whole joints after destabilization of the medial meniscus (DMM) in an FGF2-dependent manner (Figure 2B); upregulation of TSG-6 was suppressed in FGF2−/− mice
TaqMan microfluidic cards were prepared for a number of known inflammatory and FGF2-dependent genes previously found to be upregulated in whole joints following DMM or after in vitro cartilage injury [16,17]
Summary
Tumor necrosis factor alpha (TNF-α) stimulated gene 6 (TSG-6) is a secreted product of TNF-α–treated cells [1], which encodes for a 35 kDa multifunctional protein, consisting of Link and CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) modules [2,3,4]. In murine models of inflammatory arthritis, TSG-6 has been shown to protect the joint against damage. Delivery of recombinant protein led to a reduction in proteoglycan-induced arthritis, whereas deletion of TSG-6 in the same murine model led to increased severity of arthritis [8,9]. Chondroprotection was seen in mice overexpressing TSG-6 in a collagen-induced arthritis model [10] and in antigen-induced arthritis wherein mice expressing a cartilage-specific transgene of TSG-6 had reduced aggrecan and cartilage degradation [11]. TSG-6 has been detected at high levels in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis (OA; 12,13), and TSG-6 levels are highly elevated in human synovial fluid following joint injury [14]. TSG-6 enzymatic activity, detected by the transfer of heavy chains from inter-alpha-inhibitor
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