On November 18, Dr. Peijun Ren from the School of Public Health at Shanghai Jiao Tong University and collaborators published a research paper titled “Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis” in Nature Aging. The team used single-cell whole genome sequencing (sc-WGS) and analysis techniques to profile the somatic mutational landscape of articular chondrocytes in aging and osteoarthritis (OA), revealing age-associated mutation accumulation and distinctive mutational features in OA, and highlighting the important role of DNA damage in the pathogenesis of OA. The researchers found that each chondrocyte carries thousands of SNVs and hundreds of InDels, with mutation burden increasing with age. The overall mutational burden is comparable to various human cell types, and the age-related accumulation is consistent with findings in other tissues and cell types. A universal clock-like mutational signature (SBS5) was consistently detected in chondrocytes. Surprisingly, OA chondrocytes exhibited lower overall mutation burden and reduced InDel-associated signatures compared with non-OA controls.

Somatic mutations accumulate in human tissues throughout life due to errors in DNA replication and repair, and growing evidence links this age-related genomic instability to multiple degenerative diseases. With aging, DNA strand breaks progressively accumulate in chondrocytes, and these breaks are more abundant in OA cartilage than in non-OA tissue. Previous studies have shown defective DNA damage repair capacity in OA chondrocytes, whereas enhancing repair activity can improve chondrocyte homeostasis and delay OA progression. In osteoarthritis (OA), cartilage degradation, and chondrocyte loss due to apoptosis exacerbate tissue dysfunction and contribute to disease progression. Together with the observed lower InDel frequency in OA chondrocytes, the study reasons that the mutational characteristics of OA chondrocytes likely reflect a convergence of impaired DNA repair capacity, progressive DNA damage accumulation due to insufficient repair, and the preferential apoptosis of cells carrying extensive genomic damage.

Original article: https://doi.org/10.1038/s43587-025-01011-z