OBJECTIVE: Cellular senescence in cartilage is a driver of knee 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, aiming to identify senolytic drugs for their selective elimination.
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 the PL mechanism. PL effects were 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 the OA rat meniscus and cartilage. PL outperformed other senolytics, selectively eliminating senescent MCs and CCs without harming normal cells. Transcriptomic analysis revealed that PL altered reactive oxygen species (ROS)-related pathways specifically in senescent cells, while cotreatment with ROS scavengers completely blocked PL-induced cell death. In human OA MCs and CCs, PL reduced senescent cell numbers 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 provides the first direct evidence of meniscal senescence in OA and demonstrates that PL can selectively clear senescent MCs and CCs, attenuating OA progression. These findings highlight the strong potential of PL as a disease-modifying OA drug.
