title: Single impact cartilage trauma and TNF-α: interactive effects do not increase early cell death and indicate the need for bi-/multidirectional therapeutic approaches.
abstract: Blunt trauma of articular cartilage, often resulting from accidents or sports injuries, is associated with local inflammatory reactions and represents a major risk factor for development of post-traumatic osteoarthritis. TNF-α is increased in synovial fluid early after trauma, potentiates injury-induced proteoglycan degradation and may act proapoptotic under permissive conditions. We asked whether TNF-α also influences chondrocyte death, gene expression of catabolic and anabolic markers and the release of proinflammatory mediators in the early post-traumatic phase. Interactive effects of a defined single impact trauma (0.59 J) and TNF-α (100 ng/ml) on human early-stage osteoarthritic cartilage were investigated in vitro over 24 h. Exposure of traumatized cartilage to TNF-α did not increase chondrocyte death. IL-6-synthesis was augmented by trauma, TNF-α and combined treatment. The impact increased the release of PGE2 and PGD2 in the presence and absence of TNF-α to a similar extent while TNF-α alone showed no effect. In contrast, NOS2A-expression and nitric oxide (NO)-release were not affected by trauma but significantly increased by TNF-α. Expression of OPG and RANKL was not affected by TNF-α but modulated by trauma. TNF-α with and without trauma significantly induced MMP1 gene expression. These results indicate that TNF-α does not potentiate early cell death in early-stage osteoarthritic cartilage after blunt injury. However, trauma and TNF-α showed independent and interactive effects concerning prostaglandin and NO release. TNF-α probably contributes to cartilage degradation after trauma by an early induction of MMP1 gene expression. Our study confirms that an anti-TNF-α therapy may have inhibitory effects on catabolic and, partly, on inflammatory processes after a single impact trauma. As TNF-α does not contribute to the loss of chondrocytes in the initial post-traumatic phase, a combination with pharmaco-therapeutic strategies reducing early cell death could be reasonable.
authors.affiliation: Division for Biochemistry of Joint and Connective Tissue Diseases,                     Department of Orthopedics, University of Ulm, Ulm, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Hogrefe
authors.forename: Helga
authors.initials: H
authors.lastname: Joos
authors.forename: Vennila
authors.initials: V
authors.lastname: Maheswaran
authors.forename: Lutz
authors.initials: L
authors.lastname: Dürselen
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
authors.forename: Rolf E
authors.initials: RE
authors.lastname: Brenner
mesh_terms: D000368:Aged; D017209:Apoptosis; D002358:Cartilage, Articular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D019902:Chondrocytes / Q000378:metabolism / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D053244:Osteoprotegerin / Q000378:metabolism; D015230:Prostaglandin D2 / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D053245:RANK Ligand / Q000378:metabolism; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D054834:Lipocalins; D009566:Nitrates; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D015230:Prostaglandin D2