Osteoarthritis patients with high haemoglobin A1c have increased Toll-like receptor 4 and matrix metalloprotease-13 expression in the synovium

PURPOSE: While research has identified diabetes mellitus (DM) as a risk factor for knee osteoarthritis (KOA), the underlying mechanisms are not fully understood. Studies suggest that Toll-like receptor 4 (TLR4) expression is elevated in osteoarthritic lesions of OA patients and in target tissues of insulin resistance such as adipose tissue and skeletal muscle in patients with DM. TLR4 is associated with inflammation and catabolic response via regulation of matrix metalloproteases (MMPs). We hypothesized that TLR4 and MMP expression may be increased in the synovial tissue (SYN) of KOA patients with diabetic pathology. We therefore investigated TLR and MMP expression in the SYN of KOA patients with and without high haemoglobin A1c concentrations. PATIENTS AND METHODS: A total of 171 patients radiographically diagnosed with KOA were grouped based on their HbA1c concentration (HbA1c ≥6.5 and HbA1c <6.5). We used real-time polymerase chain reaction to compare the expression of TLRs (TLR2, TLR4) and MMPs (MMP2, MMP3, MMP9 and MMP13) in patients’ SYN between the two groups. MMP13 regulation by the TLR4 ligand, lipopolysaccharide (LPS), in SYN cells was examined in culture by stimulating SYN cells with LPS or vehicle (culture medium) for 24 h. RESULTS: The expression of TLR4 and MMP13 in the HbA1c ≥6.5 group was significantly elevated compared to that in the HbA1c <6.5 group. In contrast, TLR2, MMP2, MMP3 and MMP9 expression levels were similar between the groups. MMP13 mRNA and MMP13 protein levels in SYN cells were significantly higher following stimulation with LPS compared to vehicle. CONCLUSIONS: TLR4 and MMP13 expression were elevated in the synovium of osteoarthritis patients with high HbA1c concentrations. Our results may provide insight into the pathology of OA patients with DM.