Restoring hyaline cartilage integrity remains a significant challenge in regenerative medicine. When damaged, the defect is replaced by fibrosis connective tissue, resulting in a loss of the biomechanical properties of the cartilage. This review examines the intricate molecular mechanisms underlying reparative chondrogenesis and presents examples from a variety of animal species. It provides a comprehensive overview of the signaling pathways and cellular responses that promote cartilage repair, showcasing the regenerative abilities of fish and amphibians, including the little skate and axolotl, and surprising cases of chondrogenesis in mammals like the naked mole-rat and the Acomys mouse. Unraveling the dynamic interplay between growth factors, cytokines, and extracellular matrix components will shed light on the complex signaling pathways controlling reparative chondrogenesis. The comparative analysis presented in this review reveals both conserved and species-specific molecular pathways involved in cartilage regeneration. This provides valuable information for translational studies. By uncovering the genetic and epigenetic determinants governing extreme examples of reparative chondrogenesis, this review provides a comprehensive framework for developing therapeutic strategies to improve cartilage repair in humans.
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