Toll-like receptor 4 promotes high glucose-induced catabolic and inflammatory responses in chondrocytes in an NF-κB-dependent manner

Diabetes is an independent risk factor for knee osteoarthritis (OA), and hyperglycaemia-induced inflammation is considered to play an important role in their connection. The Toll-like receptor 4 (TLR4) regulates inflammatory responses in several pathological conditions including diabetes and OA. However, its role in diabetes-associated OA is poorly understood. In this study, we found that TLR4 expression was higher in OA cartilage from patients with type 2 diabetes mellitus (T2DM) than that from non-T2DM patients. Similarly, its expression was induced in primary mouse chondrocytes treated with high glucose, which suggests that TLR4 upregulation in T2DM-associated OA cartilage may originate from hyperglycaemia stimulation. We further discovered that TLR4 promoted high glucose-induced catabolic and inflammatory responses in chondrocytes, and mechanistically, these effects could be explained by the exacerbated activation of the transcription factor nuclear factor kappa B (NF-κB) pathway, since its inhibition by Bay 11-7082 abrogated TLR4 effects on high glucose-treated chondrocytes. Taken together, these findings may reveal a promotive role of TLR4 in regulating hyperglycaemia-induced catabolism and inflammation in T2DM-associated OA, and also implicate that TLR4 inhibition might be of therapeutic significance in treating T2DM-associated OA.