Cartilage cells in osteoarthritis carry fewer DNA mutations than healthy ones, a surprise finding

Somatic mutations, the DNA changes cells acquire over a lifetime, are now linked to many diseases besides cancer. Osteoarthritis (OA) is a very common age-related disease. Its prevalence rose about 9% worldwide between 1990 and 2017, and its causes are poorly understood. OA cartilage has long been known to show chromosomal abnormalities, but no one had measured point mutations in individual cartilage cells with modern single-cell methods.

The team studied chondrocytes, the cells that maintain cartilage, from the femoral heads of 17 people undergoing hip replacement. Nine had hip OA and eight had osteonecrosis of the femoral head and served as non-OA controls. In four OA donors, cartilage was collected from both a damaged (lesion) and a visually normal (non-lesion) site. In the other five, the damage was too severe to find normal cartilage. Single cells were sequenced using single-cell multiple displacement amplification (SCMDA), a method that avoids common artifacts. Bulk DNA from the same cartilage was sequenced to subtract inherited variants. Overall, 100 single chondrocytes (38 control, 42 OA lesion, 20 OA non-lesion) and 21 bulk samples were sequenced at roughly 31× depth. Coverage was broadly uniform, apart from the expected dips near centromeres.

The main results were as follows. Both SNVs and small InDels accumulated with age in chondrocytes and showed a clock-like mutational signature, consistent with other human tissues. Surprisingly, the age-related accumulation rate in OA chondrocytes was lower than in non-OA control chondrocytes. Mutational signatures and Gene Ontology term enrichment also differed between OA and control samples. The authors also report elevated apoptosis in OA chondrocytes, in line with earlier reports of increased DNA damage in OA. They propose that damaged cells are selectively eliminated, which would lower the mutation burden among surviving cells.

If confirmed, the work suggests that OA is not simply a matter of more mutations. Cell loss and selection against heavily damaged chondrocytes may help drive cartilage degeneration, and DNA damage response and cell survival pathways could become research targets. The study also gives the first single-cell reference for somatic mutation in human cartilage.

The main caveats are the small number of donors and cells, and the use of osteonecrosis patients rather than healthy cartilage as controls. Only SNVs and small InDels were analysed, so structural variants and chromosomal changes are not captured. The apoptosis-elimination explanation is a hypothesis rather than a demonstrated mechanism. The data are cross-sectional and from end-stage disease, which limits causal conclusions.