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

Abstract

ObjectiveOsteoarthritis (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.MethodsProteomic 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.ResultsIn 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.ConclusionThis 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.

Proteomics in orthopedic research: Recent studies and their translational implications

“…Nerve growth factor can be induced in chondrocytes when exposed to TGF-β suggesting that this could be one possible mechanism behind the significant pain in OA since typically nervous tissue is not present in cartilage. 11 Di 14 and colleagues investigated if the subtypes of chondrocytes exhibited different phenotypes under different mechanical loading conditions. They studied articular cartilage from patients with OA, cell culture, and mouse tissue.…”

“…Moving forward, targeting OAHCs may be a promising avenue for delaying or possibly treating OA when under abnormal weight bearing conditions. 14 Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) plays a major role in purine metabolism and subsequently cell proliferation, differentiation, and apoptosis. [15][16][17][18] In an effort to better understand the molecular mechanisms of Enpp1, Gao et al 19 studied cartilage of homozygous Enpp1 knockout mouse models using proteomics and KEGG pathway enrichment analysis.…”