Blocking 15-hydroxy prostaglandin dehydrogenase (15-PGDH) with a small-molecule inhibitor reversed cartilage degeneration and reduced osteoarthritis pain in mice. The treatment shifted chondrocyte populations from hypertrophic cells that express high 15-PGDH toward matrix-synthesizing articular chondrocytes that rebuild cartilage structure. This represents a significant departure from current osteoarthritis paradigms that focus on slowing degeneration rather than promoting regeneration. The mechanism involves reprogramming existing cartilage cells rather than recruiting stem cells, suggesting the joint retains latent regenerative capacity that can be pharmacologically awakened. Single-cell sequencing revealed specific chondrocyte subpopulations that respond to 15-PGDH inhibition, providing molecular targets for therapeutic development. However, translation to humans faces substantial hurdles given the complexity of human osteoarthritis compared to mouse models. The 400 million people worldwide with osteoarthritis currently have few disease-modifying options beyond joint replacement surgery. If this pathway proves viable in human trials, 15-PGDH inhibitors could represent the first truly regenerative osteoarthritis therapy, potentially transforming treatment from symptom management to tissue restoration.