Piperlongumine attenuates osteoarthritis
Objective: Cellular senescence in cartilage is a driver of osteoarthritis (OA) progression, but its role in the meniscus remains unclear. This study investigated whether senescent cells accumulate in both meniscus and cartilage during OA and aimed to identify senolytic drugs to selectively eliminate them. Methods: Senescence and senescence-associated secretory phenotype (SASP) marker expression was assessed in meniscus and cartilage of OA-induced rats. Rat meniscus cells (MCs) and chondrocytes (CCs) were rendered senescent with H2O2 and treated with candidate senolytics, including piperlongumine (PL). Transcriptomic analysis was performed to explore PL's mechanism. The effect of PL was also tested in OA patient-derived MCs and CCs. Finally, PL was administered to OA rats to evaluate its effect on OA progression. Results: Senescence markers (p16, p21) and SASP factors (MMP3, MMP9, MMP13, MCP1) were upregulated in both meniscus and cartilage of OA rats. PL selectively eliminated senescent MCs and CCs without harming normal cells, outperforming other senolytics. Transcriptomic analysis revealed that PL altered reactive oxygen species (ROS)-related pathways specifically in senescent cells, and co-treatment with ROS scavengers completely blocked PL-induced cell death. In human OA MCs and CCs, PL reduced senescent cells and enhanced glycosaminoglycan production. In OA rats, PL treatment alleviated meniscus and cartilage degeneration, decreased senescence and SASP marker expression, and suppressed synovitis. Conclusion: This study provided the first direct evidence of meniscal senescence in OA and demonstrated that PL selectively cleared senescent MCs and CCs, attenuating OA progression. These findings highlight the strong potential of PL as a disease-modifying OA drug.
Objective: Cellular senescence in cartilage is a driver of osteoarthritis (OA) progression, but its role in the meniscus remains unclear. This study investigated whether senescent cells accumulate in both meniscus and cartilage during OA and aimed to identify senolytic drugs to selectively eliminate them. Methods: Senescence and senescence-associated secretory phenotype (SASP) marker expression was assessed in meniscus and cartilage of OA-induced rats. Rat meniscus cells (MCs) and chondrocytes (CCs) were rendered senescent with H2O2 and treated with candidate senolytics, including piperlongumine (PL). Transcriptomic analysis was performed to explore PL's mechanism. The effect of PL was also tested in OA patient-derived MCs and CCs. Finally, PL was administered to OA rats to evaluate its effect on OA progression. Results: Senescence markers (p16, p21) and SASP factors (MMP3, MMP9, MMP13, MCP1) were upregulated in both meniscus and cartilage of OA rats. PL selectively eliminated senescent MCs and CCs without harming normal cells, outperforming other senolytics. Transcriptomic analysis revealed that PL altered reactive oxygen species (ROS)-related pathways specifically in senescent cells, and co-treatment with ROS scavengers completely blocked PL-induced cell death. In human OA MCs and CCs, PL reduced senescent cells and enhanced glycosaminoglycan production. In OA rats, PL treatment alleviated meniscus and cartilage degeneration, decreased senescence and SASP marker expression, and suppressed synovitis. Conclusion: This study provided the first direct evidence of meniscal senescence in OA and demonstrated that PL selectively cleared senescent MCs and CCs, attenuating OA progression. These findings highlight the strong potential of PL as a disease-modifying OA drug.
Institute of Science Tokyo