Elevation of α-1,3 fucosylation promotes binding ability of TNFR1 to TNF-α and contributes to osteoarthritic cartilage destruction and apoptosis

Abstract Background: Osteoarthritis (OA) is characterized by ECM degradation in chondrocytes and inflammation of the synovial membrane. Fucosylation is a main type of glycosylation, and is involved in a variety of pathological processes, including inflammation and cancer. However, whether fucosylation impacts the OA process is unknown. Methods: Total proteins were extracted from cartilage samples obtained from patients with OA (n = 11), OA rabbit models at different time points (n = 12). The OA-associated abnormal glycopatterns were evaluated by lectin microarray and lectin blot. Expression of fucosyltransferases involved in the synthesis of α-1,3 fucosylation were assessed by semi-qPCR. The α-1,3 fucosylation mediated by FUT10 was interrupted by transfection of siRNA; and the effect of α-1,3 fucosylation on OA-associated events was assessed. The TNFR1 antibody microarray was fabricated to investigate the effect of α-1,3 fucosylation on the binding ability of TNFR1 to TNF-α.Results: Elevated α-1,3 fucosylation is observed in cartilage from OA patients, rabbit models and chondrocytes induced by TNF-α (fold change> 2, p< 0.01). The overexpression of FUT10 contributes to this alteration. Downregulation of FUT10 impaired the binding ability of TNFR1 to TNF-α, impeded activation of the NF-κB and P38/JNK-MAPK pathways and eventually retarded ECM degradation, senescence and apoptosis of chondrocytes induced by TNF-α. Conclusion: The elevation of α-1,3 fucosylation is not only a characteristic of OA but also impacts the OA process. Our work provides a new positive feedback loop of “inflammation conditions/TNF-α/FUT10/α-1,3 fucosylation of TNFR1/NF-κB and P38/JNK-MAPK pathways/proinflammatory processes” that contributes to ECM degradation and apoptosis of chondrocytes.