Glycyrrhizin mitigates inflammatory bone loss and promotes expression of senescence-protective sirtuins in an aging mouse model of periprosthetic osteolysis

Abstract

Although periprosthetic osteolysis induced by wear debris particles is significantly elevated in senior (65+ years old) patients, most of the published pre-clinical studies were performed using young (less than three-month old) mice indicating the critical need to employ experimental models of particle-induced osteolysis involving mice with advanced age. Emerging evidence indicates that currently available antiresorptive bone therapies have serious age-dependent side effects. However, a resurgence of healthcare interest has occurred in glycyrrhizin (GLY), a natural extract from the licorice roots, as alternative sources of drugs for treating inflammatory bone lytic diseases and prevention of cellular senescence. This study investigated the effects of GLY on inflammatory bone loss as well as expression patterns of senescence-associated secretory phenotype and senescence-protective markers using an experimental calvarium osteolytic model induced in aged (twenty-four-month-old) mice by polymethylmethacrylate (PMMA) particles. Our results indicate that local treatment with GLY significantly diminished the size of inflammatory osteolytic lesions in aged mice via the number of CXCR4+OCPs and Tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts. Furthermore, GLY dramatically decreased the amounts of senescence-associated secretory phenotype markers, including pro-inflammatory macrophage migration inhibitory factor (MIF) chemokine, and cathepsins B and K in the bone lesions of aged mice. By contrast, GLY significantly elevated expression patterns of senescence-protective markers, including homeostatic stromal derived factor-1 (SDF-1) chemokine, and sirtuin-1, and sirtuin-6, in the PMMA particle-induced calvarial lesions of aged mice. Collectively, these data suggest that GLY can be used for the development of novel therapies to control bone loss and tissue aging in senior patients with periprosthetic osteolysis.

A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues

“…This is perhaps not surprising given the importance of MIF as a pro-inflammatory cytokine, inhibitor of p53, and positive regulator of NF-κB 72 . MIF appears to be pivotal for cellular senescence, aging, and joint inflammation; however, its presence has been associated with a beneficial effect on the healthy lung and in MSCs [73][74][75][76][77][78] . Of note, recent evidence indicates an important role for MIF signaling in immune Fig.…”

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

“…71 MIF appears to be pivotal for cellular senescence, aging, and joint inflammation; however, its presence been associated with a beneficial effect on the healthy lung and in MSCs. [72][73][74][75][76][77] Of note, recent evidence indicates an important role for MIF signaling in immune evasion by tumors 78 and parasites, 79 raising the possibility that increased MIF expression by multiple senescent cell types may play a role in the ability of senescent cells to resist immune clearance, particularly with aging, 53 and this possibility warrants further study. Importantly, we also used Mif expression to validate our in silico predictions based on the scRNA-seq analyses, and confirmed both an increase in Mif expression with aging in murine bone as well as a reduction in Mif mRNA levels following genetic clearance of senescent cells.…”

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

“…71 MIF appears to be pivotal for cellular senescence, aging, and joint inflammation; however, its presence has been associated with a beneficial effect on the healthy lung and in MSCs. [72][73][74][75][76][77] Of note, recent evidence indicates an important role for MIF signaling in immune evasion by tumors 78 and parasites, 79 raising the possibility that increased MIF expression by multiple senescent cell types may play a role in the ability of senescent cells to resist immune clearance, particularly with aging, 53 and this possibility warrants further study. Importantly, we also used Mif expression to validate our in silico predictions based on the scRNA-seq analyses, and confirmed both an increase in Mif expression with aging in murine bone as well as a reduction in Mif mRNA levels following genetic clearance of senescent cells.…”