An EP2 receptor-selective prostaglandin E sub(2) agonist induces bone healing

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-05, Vol.100 (11), p.6736-6740
• Main Authors: Paralkar, V M, Borovecki, F, Ke, H Z, Cameron, KO, Lefker, B, Grasser, WA, Owen, T A, Li, M, DaSilva-Jardine, P, Zhou, M, Dunn, R L, Dumont, F, Korsmeyer, R, Krasney, P, Brown, T A, Plowchalk, D, Vukicevic, S, Thompson, D D
• Format: Article
• Language: English
• ISSN: 0027-8424
• DOI: 10.1073/pnas.1037343100

The morbidity and mortality associated with impaired/delayed fracture healing remain high. Our objective was to identify a small nonpeptidyl molecule with the ability to promote fracture healing and prevent malunions. Prostaglandin E sub(2) (PGE sub(2)) causes significant increases in bone mass and bone strength when administered systemically or locally to the skeleton. However, due to side effects, PGE sub(2) is an unacceptable therapeutic option for fracture healing. PGE sub(2) mediates its tissue-specific pharmacological activity via four different G protein-coupled receptor subtypes, EP1, -2, -3, and -4. The anabolic action of PGE sub(2) in bone has been linked to an elevated level of cAMP, thereby implicating the EP2 and/or EP4 receptor subtypes in bone formation. We identified an EP2 selective agonist, CP-533,536, which has the ability to heal canine long bone segmental and fracture model defects without the objectionable side effects of PGE sub(2), suggesting that the EP2 receptor subtype is a major contributor to PGE sub(2)'s local bone anabolic activity. The potent bone anabolic activity of CP-533,536 offers a therapeutic alternative for the treatment of fractures and bone defects in patients.