Theaflavin-3,3'-digallate represses osteoclastogenesis and prevents wear debris-induced osteolysis via suppression of ERK pathway

Abstract

Peri-implant osteolysis (PIO) and the following aseptic loosening is the leading cause of implant failure. Emerging evidence suggests that receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation and osteoclastic bone resorption are responsible for particle-stimulated PIO. Here, we explored the effect of theaflavin-3,3'-digallate (TF3) on titanium particle-induced osteolysis in vivo and in vitro. Twenty-eight male C57BL/6 mice were randomly separated into four groups: sham control (sham), titanium particles only (titanium), titanium particles with low TF3 concentration (low-TF3, 1mg/kg TF3), and titanium particles with high TF3 concentration (high-TF3, 10mg/kg TF3). Two weeks later, micro-computed tomography and histological analysis were performed. Bone-marrow-derived macrophages and RAW264.7 murine macrophages were applied to examine osteoclast formation and differentiation. TF3 significantly inhibited titanium particle-induced osteolysis and prevented bone destruction compared with titanium group. Interestingly, the number of mature osteoclasts reduced after treatment with TF3 in vivo, suggesting osteoclast formation might be inhibited by TF3. In vitro, TF3 suppressed osteoclast formation, polarization and osteoclastic bone resorption by specifically targeting the RANKL-induced ERK signal pathway. Collectively, these results suggest that TF3, a natural active compound derived from black tea, is a promising candidate for the treatment of osteoclast-related osteolytic diseases, such as wear debris-induced PIO.

Statement of significance: Total joint arthroplasty is widely accepted for the treatment of end-stage joint diseases. However, it is reported that aseptic loosening, initiated by peri-implant osteolysis, is the major reason for prosthesis failure. Although the pathophysiology of PIO remains unclear, increasing evidence indicates that osteoclasts are excessively activated at the implant site by wear debris from materials. Here, we demonstrated that theaflavin-3,3'-digallate, a natural active compound derived from black tea, inhibited osteoclast formation and osteoclastic bone resorption mainly via suppressing the ERK pathway. Moreover, the findings of this study have confirmed for the first time that theaflavin-3,3'-digallate has a protective effect on particle-induced osteolysis in a mouse calvarial model, thus preventing bone loss. These results indicate that theaflavin-3,3'-digallate may be a suitable therapeutic agent to treat wear debris-induced peri-implant osteolysis.

Keywords: ERK pathway; Peri-implant osteolysis; RANKL; Theaflavin-3,3′-digallate; Wear debris.