The paper is behind a paywall.
Could a person post / link a copy to the paper
Editor’s summary
Osteoarthritis is a common debilitating disease that is difficult to treat effectively. Singla et al. found that treatment with a small-molecule inhibitor of the enzyme 15-hydroxy prostaglandin dehydrogenase (15-PGDH) could decrease pain and promote regeneration of cartilage in aged or young mice after injury. The inhibitor also decreased inflammation and promoted regeneration in explants from human patients with osteoarthritis. Characterization of cellular changes indicated that alterations in gene expression in existing chondrocytes, rather than activation of stem or progenitor cells, were responsible for the regenerative effects. —L. Bryan Ray
Structured Abstract
INTRODUCTION
Cartilage is one of the least regenerative tissues, which presents a challenge of fundamental interest and a major unmet medical need as osteoarthritis (OA) afflicts mobility in one out of five adults. There are limited effective disease modifying therapies for OA that restore cartilage function and treatment options are limited to pain management or eventual joint replacement. We report that systemic or local inhibition of the prostaglandin-degrading enzyme, 15-hydroxy prostaglandin dehydrogenase (15-PGDH), with a small-molecule inhibitor (PGDHi) leads to robust regeneration of articular cartilage in OA in young and aged mice and human explants.
RATIONALE
We sought to determine whether the age-associated increase in 15-PGDH—a catabolic enzyme that degrades the lipid metabolite prostaglandin E2 (PGE2) and is a molecular driver of aging in muscle—also plays a role in cartilage dysfunction with age. We observed increased 15-PGDH expression in aged and injured cartilage and postulated that inhibition of 15-PGDH with a small-molecule drug would lead to cartilage regeneration.
RESULTS
Using single-cell RNA-seq and spatial proteomics by multiplexed tissue imaging [co-detection by indexing (CODEX)] we identified a detrimental cartilage-resident 15-PGDH–expressing hypertrophic chondrocyte population in mouse OA resulting from ACL injury or aging. Short-term systemic or local inhibition of 15-PGDH with a small-molecule inhibitor (PGDHi) led to extensive cartilage regeneration. Notably, the regenerated cartilage was hyaline articular cartilage, not functionally inferior fibrocartilage, as shown by collagen II and specific proteoglycan synthesis. Pain, the most common clinical symptom of OA, was diminished in three well-established assays. This finding, which contradicts prior reports suggesting that PGE2 causes pain, is likely due to the physiologic modulation of PGE2 levels afforded by inhibiting its degrading enzyme, 15-PGDH, which obviates inflammation and inflammatory cytokines. Importantly, PGDH inhibitor treatment caused a change in chondrocyte composition of the OA joint with a decrease in the proportion of deleterious hypertrophic-like and fibrogenic chondrocytes and an increase in articular chondrocytes that secrete extracellular matrix essential to cartilage function. PGE2-mediated cartilage regeneration occurs through changes in gene expression in existing cell populations, which is distinct from its action on stem and progenitor cell expansion in muscle or blood regeneration.
Our results suggest that a shift in the proportions of chondrocytes present in the joint might suffice to regenerate cartilage. We observed similar changes in gene expression in chondrocytes present in human cartilage explants obtained from OA patients undergoing knee replacement, underscoring the clinical potential of the small-molecule 15-PGDH inhibitor as a therapeutic candidate for OA.
CONCLUSION
Our findings highlight that inhibition of 15-PGDH—an enzyme that drives tissue aging, a “gerozyme”—leads to cartilage regeneration in aged mouse OA joints, in joints of young adult mice with posttraumatic OA (PTOA) resulting from an ACL tear, a common problem experienced by athletes, and in human OA patient–derived joint explants. Inhibition of 15-PGDH through a small-molecule drug that is highly specific and readily delivered to the joint represents a new therapeutic approach for OA that is readily amenable to translation to the clinic.
Inhibition of the gerozyme 15-PGDH leads to cartilage regeneration through gene expression changes and a shift in cell composition from fibrocartilage to hyaline cartilage.
Abstract
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.