Effects of Glycyrrhizin on Particle-induced Osteolysis in Relation to Aging

Objectives: It is commonly accepted that patients aged >65 years are more prone to develop cement particle-induced osteolysis than young patients. Because most of the published pre-clinical studies are performed using young animals (< 12-weeks-old), our knowledge about the impact of aging on pro-inflammatory cytokines production in particle-induced lesions is limited. Growing evidence supports that extracellular release of high mobility group protein B1 (HMGB1) amplifies a senescence-associated inflammation. However, glycyrrhizin serves as a natural inhibitor of pro-inflammatory activity of extracellular HMGB1. The present study aimed to evaluate the impact of HMGB1 and glycyrrhizin on particle-induced osteolytic lesions in aged mice.
Methods: PMMA cement particles were injected over the calvaria into aged (twenty-four-month-old) C56BL/6 mice. Then, mice were locally injected every other day with various concentrations of glycyrrhizin. The levels of inflammation as well as bone loss were evaluated by cutting-edge in situ Brucker’s micro-CT and intravital imaging systems and then by conventional Real-Time and ELISA assays after ten days of PMMA particle placement. In addition, the expression of anti-aging sirtuins (SIRT 1 and SIRT 6) mRNA was also evaluated.
Results: Elevated production of HMGB1 was detected in PMMA-particle induced calvarial osteolytic lesions in relation to aging. In contrast, application of glycyrrhizin significantly downregulated production of TNF-a, IL-6 and IL-1b pro-inflammatory cytokines in the experimental model of PMMA particle-induced osteolytic lesions in aged mice. Furthermore, glycyrrhizin significantly reduced activities of cathepsin B and cathepsin K and upregulated expression of anti-aging SIRT 1 and SIRT 6 mRNA genes in the calvarial lesions of aged mice.
Conclusions: HMGB1 increased the productions of pro-inflammatory cytokines and cathepsins activity in PMMA particles-induced calvarial bone lesions of aged mice which can be suppressed by glycyrrhizin, possibly leading to the development of anti-bone loss regimens in age-associated osteolysis.