Sophocarpine Prevents Aseptic Implant Loosening By Suppressing Osteoclastogenesis And Inflammation

Artificial joint arthoplasty is currently the most effective means for the treatment of severe joint degenerative diseases,joint damage,and bone and joint destruction caused by other diseases.Prosthetic aseptic loosening is the most common cause leading to the failure of arthoplasty.Revision is still the best way to treat prosthesis loosening to date.The mechanism is still unclear,and it is generally believed that osteolysis is related to wear debris generated from joint surface.Wear debris induces inflammatory reactions in the tissues surrounding the prosthesis,promotes the excessive formation of osteoclasts and bone resorption,triggering osteolysis and pseudomembrane formation around the prosthesis,finally resulting in prosthesis loosening.Therefore,inhibiting wear debris-induced inflammatory response and osteoclastogenesis could prevent prosthesis loosening.Sophocarpine is derived from plants and it is one of the main active ingredients of Sophora flavescens.In this study,we examined the effect of sophocarpine on inflammatory response and bone resorption to verify its therapeutic effect on prosthesis loosening.In this study,we found that sophocarpine can inhibit RANKL-induced osteoclast formation in vitro,especially at the early stage.To explore the effect of sophocarpine on osteoclasts activities,we seeded mature osteoclasts on bone slice and treated with sophocarpine.The results showed that sophocarpine can inhibit bone resorption.To further explore the molecular mechanism of sophocarpine in inhibiting osteoclastogenesis,we used Western Blot to screen the main signaling pathways for osteoclastogenesis.The results showed that the inhibitory effect of sophocarpine on osteoclasts is achieved by suppressing the nuclear factor kappa B(NF-κB)pathway.Since inflammatory response is another cause of aseptic loosening,we here established Ti-induced inflammatory response in macrophage.The results showed that sophocarpine can inhibit the release of Ti-induced inflammatory factors.We further used Western Blot and immunofluorescence to explore its mechanism.The results showed that the anti-inflammatory effect of sophocarpine was also achieved through inhibition of NF-κB signaling pathway.Subsequently,we established an wear-induced rat femoral aseptic loosening model.We found that sophocarpine treatment could significantly increased prosthetic bone mineral density and enhance stability of prosthesis,as well as suppressed the release of inflammatory factors and bone resorptive-related turnover.Micro-CT results showed that sophocarpine can inhibit wear-induced bone loss,while histological results show that sophocarpine can inhibit the formation of pseudomembranes and wear-induced osteoclastogenesis in vivo.Sophocarpine could improve bone-implant contact.Immunohistochemistry showed that sophocarpine inhibited the activation of NF-κB pathway in vivo.As the artificial joint replacements increase,aseptic prosthesis loosening will also increase.It is importance to prevent aseptic loosening and prolong the life span of joints.Our study shows that sophocarpine can effectively inhibit the aseptic prosthesis loosening caused by inhibiting the inflammatory reaction and osteoclastic bone resorption.Therefore,sophoraine can potentially be a new drug for the treatment of aseptic loosening and osteolysis-related diseases.