Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration
- Mamta Singla
- Yu Xin Wang
- Elena Monti
- Yudhishtar Bedi
- Pranay Agarwal
- Shiqi Su
- Sara Ancel
- Maiko Hermsmeier
- Nitya Devisetti
- Akshay Pandey
- Mohsen Afshar Bakooshli
- Adelaida R. Palla
- Stuart Goodman
- Helen M. Blau
- Nidhi Bhutani
2025-11-27
Aging or injury to the joints can lead to cartilage degeneration and osteoarthritis (OA), for which there are limited effective treatments. We found that expression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH) is increased in the articular cartilage of aged or injured mice. Both systemic and local inhibition of 15-PGDH with a small-molecule inhibitor (PGDHi) led to regeneration of articular cartilage and reduction in OA-associated pain. Using single-cell RNA-sequencing and multiplexed immunofluorescence imaging of cartilage, we identified the major chondrocyte subpopulations. Inhibition of 15-PGDH decreased hypertrophic-like chondrocytes expressing 15-PGDH and increased extracellular matrix–synthesizing articular chondrocytes. Cartilage regeneration appears to occur through gene expression changes in preexisting chondrocytes, rather than stem or progenitor cell proliferation. 15-PGDH inhibition could be a potential disease-modifying and regenerative approach for osteoarthritis.