Cartilage tissue from sites of weight bearing in patients with osteoarthritis exhibits a differential phenotype with distinct chondrocytes subests

OBJECTIVE: Osteoarthritis (OA) is a degenerative joint disease associated with excessive mechanical loading. The aim here was to elucidate whether different subpopulations of chondrocytes exhibit distinct phenotypes in response to variations in loading conditions. Furthermore, we seek to investigate the transcriptional switches and cell crosstalk among these chondrocytes subsets. METHODS: Proteomic analysis was performed on cartilage tissues isolated from weight-bearing and non-weight-bearing regions. Additionally, single-cell RNA sequencing was employed to identify different subsets of chondrocytes. For disease-specific cells, in vitro differentiation induction was performed, and their presence was confirmed in human cartilage tissue sections using immunofluorescence. The molecular mechanisms underlying transcriptional changes in these cells were analysed through whole-transcriptome sequencing. RESULTS: In the weight-bearing regions of OA cartilage tissue, a subpopulation of chondrocytes called OA hypertrophic chondrocytes (OAHCs) expressing the marker genes SLC39A14 and COL10A1 are present. These cells exhibit unique characteristics of active cellular interactions mediated by the TGFβ signalling pathway and express OA phenotypes, distinct from hypertrophic chondrocytes in healthy cartilage. OAHCs are mainly distributed in the superficial region of damaged cartilage in human OA tissue, and on TGFβ stimulation, exhibit activation of transcriptional expression of iron metabolism-related genes, along with enrichment of associated pathways. CONCLUSION: This study identified and validated the existence of a subset of OAHCs in the weight-bearing area of OA cartilage tissue. Our findings provide a theoretical basis for targeting OAHCs to slow down the progression of OA and facilitate the repair of cartilage injuries.