15-PGDH inhibition in osteoarthritis: PGE2 skeletal interoception, cartilage regeneration and compartment-managed disease modification.

Osteoarthritis is a whole-joint disease in which cartilage loss, synovial inflammation, subchondral bone remodelling and pain-related neural changes co-evolve, yet structural improvement does not reliably translate into pain relief. This Review centres prostaglandin E₂ (PGE₂) skeletal interoception in the translational framework for 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibition. In skeletal interoception, PGE₂ produced in mechanically stressed bone and osteochondral tissues is sensed by prostaglandin E receptor 4 (EP4)-positive sensory afferents, relayed to central circuits and translated into altered sympathetic norepinephrine output. Because 15-PGDH catabolises PGE₂, its inhibition may prolong the persistence and spatial reach of this interoceptive cue while also acting locally on chondrocyte state. This combined local and interoceptive action offers a plausible mechanism for cartilage repair and pain modulation, but may also create compartment-specific risk when prolonged PGE₂ persists in synovium or subchondral bone. We compare 15-PGDH inhibition with upstream synthesis blockade and receptor-specific strategies, and propose that development should be organised around three checkpoints: cartilage-enriched exposure, durability under mechanical load and structure-pain coherence. Current evidence supports cautious development rather than broad generalisation; clinical translation will require compartment-resolved pharmacokinetics/pharmacodynamics, EP-receptor attribution and early surveillance for synovial, osteochondral and pain-system liabilities.