Reports that inhibition of the age-associated gerozyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) restores articular (hyaline) cartilage in aged and injured joints by reprogramming resident chondrocytes rather than activating stem cells. 15-PGDH, which increases with age and degrades prostaglandin E2 (PGE2), drives cartilage thinning, inflammation, and osteoarthritis (OA) progression. Pharmacological blockade of 15-PGDH in aged and ACL-injured mice regenerated functional cartilage, suppressed inflammatory and hypertrophic gene programs, prevented post-traumatic OA, and improved joint loading and mobility. Single-cell transcriptomic analysis revealed a shift from catabolic and fibrocartilage-producing chondrocyte populations toward a youthful, matrix-producing hyaline cartilage phenotype without stem cell involvement. Importantly, human osteoarthritic cartilage explants treated ex vivo showed reduced 15-PGDH expression and initiation of articular cartilage regeneration. Given that an oral 15-PGDH inhibitor has already demonstrated safety and biological activity in Phase I trials for age-related muscle weakness, these findings establish 15-PGDH inhibition as a disease-modifying, regenerative therapeutic strategy for osteoarthritis and age- or injury-related cartilage loss.<\/p>\n\n\n\n