Synovial advanced glycosylation end products aggravate periprosthetic infection in diabetes by upregulating...

Diabetes mellitus (DM) is a high-risk factor for periprosthetic joint infection (PJI). However, the mechanism how hyperglycemia induces or promotes PJI remains unclear. This study aimed to determine how host hyperglycemia stimulates pathogenic bacteria and thus induces PJI.

The rats were divided into 4 groups: control total knee arthroplasty (TKA) group, control PJI group, DM + TKA group, and DM + PJI group namely treating with high-sugar and high-fat diet + streptozotocin (STZ), and artificially induced PJI. After 3 weeks, bone and joint local inflammatory response, micro-CT, bacterial load, and biofilm formation were analyzed. The effects of advanced glycosylation end products (AGEs) and STF-31 on the biofilm formation of Staphylococcus aureus (S. aureus) were detected by crystal violet and confocal microscopy in vitro. In addition, the mechanism of AGEs promoting biofilm formation was explored by combined proteomics and transcriptomics analysis, and the effect of AGEs on RNAIII was further detected by constructing mutants.

In both humans and rats, we found more severe infectious responses in the knee joint specimens of patients and rats with DM + PJI when compared with those without PJI. Moreover, DM + PJI specimens showed higher levels of synovial AGEs and expression of glucose transporter 1 (GLUT1). AGEs exacerbated the localized infectious response of joints in vivo and promoted biofilm formation in vitro, whereas GLUT1 receptor inhibitors attenuated these effects. Finally, RNA-seq and proteomics revealed that RNAIII may be the target of AGEs acting on S. aureus. AGEs directly promoted biofilm formation by enhancing δ-hemolysin translated by RNAIII. In contrast, inhibition of RNAIII effectively attenuated AGEs-induced biofilm formation.

In summary, high glucose upregulates S. aureus RNAIII expression by activating the synovial GLUT1-AGEs pathway, thereby promoting S. aureus colonization and biofilm formation on the surface of articular prostheses, contributing to the onset and progression of PJI.

Our study shows the great potential of STF-31 as a specific treatment for DM + PJI, and is expected to become a new treatment method combined with antibiotics. RNAIII may be the target of AGEs-induced Staphylococcus aureus biofilm, which provides theoretical support and experimental basis for analyzing the effect of DM on PJI.