Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration

• 成果类型: Article
• 署名作者: Singla, Mamta; Wang, Yu Xin; Monti, Elena; Bedi, Yudhishtar; Agarwal, Pranay; Su, Shiqi; Ancel, Sara; Hermsmeier, Maiko; Devisetti, Nitya; Pandey, Akshay; Bakooshli, Mohsen Afshar; Palla, Adelaida R.; Goodman, Stuart; Blau, Helen M.; Bhutani, Nidhi
• 署名单位: Stanford University; Stanford Medicine; Stanford University; Stanford Medicine; Sanford Burnham Prebys Medical Discovery Institute; Sanford Burnham Prebys Medical Discovery Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adx6649
• 发表日期: 2026-03-05
• 关键词: GROWTH-PLATE; osteoarthritis; identification; pain; cells; MODEL; bone; E-2

摘要

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.