Punicalagin ameliorates wear-particle-induced inflammatory bone destruction by bi-directional regulation of osteoblastic formation and osteoclastic resorption.

Periprosthetic osteolysis (PPO) and subsequent aseptic loosening are the main causes of implant failure and revision surgery. Emerging evidence has suggested that wear-particle-induced chronic inflammation, osteoblast inhibition and osteoclast formation at the biointerface of implant materials are responsible for PPO. Punicalagin (PCG), a polyphenolic compound molecular extracted from pomegranate rinds, plays a critical role in antioxidant, anticancer and anti-inflammatory activities. However, whether PCG could attenuate chronic inflammation and bone destruction at sites of titanium-particle-induced osteolysis remains to be defined. In this study, we explored the effect of PCG on titanium-particle-induced osteolysis in vivo and osteoblast and osteoclast differentiation in vitro. We found that PCG could relieve wear-particle-induced bone destruction in a murine calvarial osteolysis model by increasing bone formation activity and suppressing bone resorption activity. PCG treatment also reduced the titanium-particle-induced inflammatory response, as demonstrated by the suppression of local and systemic expression of proinflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), and IL-6. In addition, we also observed that PCG promotes osteogenic differentiation of MC3T3-E1 cells under inflammatory conditions and inhibits RANKL-induced osteoclast formation of bone marrow-derived macrophages (BMMs). Meanwhile, the induction of the RANKL to OPG ratio was reversed by PCG treatment in vivo and in vitro, which demonstrated that PCG could also indirectly inhibit osteoclastogenesis. Collectively, our findings suggest that PCG represents a potential approach for the treatment of wear-particle-induced inflammatory osteolysis.