Inhibition of the Gerozyme 15-Prostaglandin Dehydrogenase Promotes Articular Cartilage Regeneration in Osteoarthritis due to Injury or Aging [scRNA-Seq]

Aging or injury to the joints can lead to cartilage degeneration osteoarthritis (OA), for which there are limited effective treatments. We found that expression of the gerozyme 15-Prostaglandin Dehydrogenase (15-PGDH) was 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. We used single cell RNA-sequencing and multiplexed immunofluorescence imaging of cartilage), to identify the major chondrocyte subpopulationsInhibition of 15-PGDH decreased hypertrophic-like chondrocytes expressing 15-PGDH and fibro-chondrocytes towards hyaline matrix-synthesizing articular chondrocytes. Regeneration of joint cartilage appears to occur through changes in pre-existing chondrocytes, not stem or progenitor cell proliferation.Gerozyme inhibition could be a potential identifying a disease-modifying and regenerative approach with potential utility for the treatment of osteoarthritis. Overall design: Young (3 mo.) and Aged (24-28 mo.) male mice were administered one month of once a day i.p. injection of vehicle (Control group) or the PGDH inhibitor SW033291 (SW group). Following treatment, knee joints from hindlimbs were harvested and the tissue was digested for scRNA sequencing based analysis.