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Piperlongumine attenuates knee osteoarthritis progression by eliminating senescent meniscus cells and chondrocytes
Kentaro Endo1, Nobutake Ozeki1, Hideyuki Koga2
1Center for Stem Cell and Regenerative Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
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.
Insights
Cellular senescence drives knee osteoarthritis (OA) progression in both cartilage and meniscus. Piperlongumine (PL) selectively eliminates senescent cells, reducing OA symptoms and degeneration, showing potential as a disease-modifying drug.
Area of Science:
- Biomedical research
- Osteoarthritis research
- Cellular senescence
Background:
- Cellular senescence in cartilage contributes to knee osteoarthritis (OA) progression.
- The role of cellular senescence in the meniscus during OA is not well understood.
Purpose of the Study:
- Investigate senescent cell accumulation in both meniscus and cartilage during OA.
- Identify senolytic drugs for selective elimination of senescent cells in OA.
Main Methods:
- Assessed senescence and SASP markers in OA rat meniscus and cartilage.
- Treated OA rat and patient-derived meniscus cells (MCs) and chondrocytes (CCs) with senolytics, including piperlongumine (PL).
- Utilized transcriptomic analysis to elucidate PL's mechanism and tested PL in OA rats.
Main Results:
- Senescence markers and SASP factors were upregulated in OA meniscus and cartilage.
- Piperlongumine (PL) selectively eliminated senescent cells and reduced OA progression in rats.
- PL treatment in human OA cells reduced senescence and improved glycosaminoglycan production.
Conclusions:
- Provided the first evidence of meniscal senescence in OA.
- Demonstrated PL's efficacy in selectively clearing senescent cells and attenuating OA.
- Highlighted PL's potential as a disease-modifying OA drug.
