Identification of IL-27 as potent regulator of inflammatory osteolysis associated with vitamin E-blended ultra-high molecular weight polyethylene debris of orthopedic implants

Osteolysis is a serious postoperative complication of total joint arthroplasty that leads to aseptic loosening and surgical revision. Osteolysis is a chronic destructive process occurs when host macrophages recognize the implant particles and release inflammatory mediators that increase bone-resorbing osteoclastic activity and attenuate bone-formation osteoblastic activity. Although much progress has been made on understanding molecular responses of macrophage to implant particles, pathways/signals initiating osteolysis remain poorly characterized. Transcriptomics and gene-expression profiling of these macrophages may unravel key mechanism in pathogenesis of osteolysis and aid in identifying molecular candidates for therapeutic intervention. To this end, we analyzed the transcriptional profiling of macrophages exposed to UHMWPE particles of the most common components used in bearing materials of orthopedic implants. Regulated genes in stimulated macrophages were involved in cytokine, chemokine, growth factor and receptor activities. Gene enrichment analysis suggested that stimulated macrophages elicited common gene expression signatures for inflammation and rheumatoid arthritis. Among the regulated genes, TNFSF15 and CCL20 were further characterized as molecular targets involved pathogenesis of osteolysis. Treatment of monocyte cultures with TNFSF15 and CCL20 resulted in an increase in osteoclastogenesis and bone-resorbing osteoclastic activity, suggesting their potential contribution to loosening between implant and bone tissue. RNA-seq for macrophages exposed to ultra-high molecular weight polyethylene (UHMWPE) particles and to VE-UHMWPE particles.