Type II collagen as a material-mediated instructive platform: Cartilage regeneration and fibrosis suppression via the Tp63-Cytl1 axis

A major challenge in cartilage regeneration is maintaining the hyaline cartilage phenotype and matrix over time while limiting hypertrophy and fibrosis. Here, type II collagen (Col2)-hyaluronic acid (Col2H) and type I collagen-hyaluronic acid (Col1H) sponges were compared using long-term three-dimensional chondrocyte culture, cross-species transcriptomic analysis, and functional experiments. Col2H supported longer-term chondrocyte phenotype and matrix retention than Col1H. Cytl1 was prioritized because it ranked highly in Col2H-associated analysis and was consistently downregulated during chondrocyte dedifferentiation in human and rat datasets. Functional assays, ChIP-qPCR, and co-immunoprecipitation supported involvement of an Itgb8-Nov-Tp63-Cytl1 regulatory network in the Col2-associated response. Col2H also showed preliminary cartilage-repair potential in a rabbit defect model. In human osteoarthritis cartilage, a five-gene signature comprising Cytl1, Tp63, Nov, Itgb8, and TIMP3 showed internal stability and an association with histological severity. These findings support a material-associated regulatory role for Col2H in chondrocyte phenotype and matrix maintenance.