A novel, non-prostanoid EP2 receptor-selective prostaglandin E2 agonist stimulates local bone formation and enhances fracture healing.
CP-533,536, a newly discovered, non-prostanoid EP2 receptor-selective PGE2 agonist, stimulates local bone formation and enhances fracture healing in rat models.


BACKGROUND
There is a significant medical need for agents that can stimulate local bone formation and enhance fracture healing. We tested the effects of CP-533,536, a newly discovered, non-prostanoid EP2 receptor-selective prostaglandin E2 (PGE2) agonist, in stimulating local bone formation and enhancing fracture healing in rat models.


METHODS
In the first model, a single injection of CP-533,536 at doses of 0.3, 1, or 3 mg/kg to the proximal tibial metaphysis of 6-week-old male rats was given on day 1, and the local bone anabolic effect was determined on day 7. We then tested the effects of this compound in inducing bone formation on rat periosteum of the femur. A single dose of 0.3 mg of CP-533,536 incorporated in a poly-(D,L-lactide-co-glycolide) (PLGH) matrix was injected onto the periosteum of the femur in 3-week-old male rats, and local bone formation was determined on day 14. Finally, the ability of CP-533,536 in PLGH matrix in enhancing fracture healing was tested using the rat femoral fracture model. CP-533,536 in PLGH matrix at doses of 0.05, 0.5, or 5 mg was delivered to the local fracture site on the same day of fracture, and its efficacy was evaluated on day 21.


CONCLUSIONS
A single injection of CP-533,536 at doses of 0.3, 1, or 3 mg/kg to the proximal tibial metaphysis dose-dependently stimulated local lamellar bone formation on trabecular, endocortical, and periosteal surfaces, and thus increased bone mineral content and bone strength at the injected site. Similarly, a single injection of 0.3 mg of CP-533,536 incorporated in PLGH matrix onto the periosteum of the femur induced significantly local bone formation. In the rat femoral fracture model, CP-533,536 in PLGH matrix at doses of 0.05, 0.5, and 5 mg dose-dependently increased callus size, density, and strength compared with PLGH matrix alone. These results show that CP-533,536 stimulates new bone formation on trabecular, endocortical, and periosteal surfaces and enhances fracture healing. These data reveal that EP2 receptor-selective agonists provide therapeutic potential for local bone augmentation, bone repair, and bone healing in humans.
Li
Mei
M
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA.
Ke
Hua Zhu
HZ
Qi
Hong
H
Healy
David R
DR
Li
Yan
Y
Crawford
D Todd
DT
Paralkar
Vishwas M
VM
Owen
Thomas A
TA
Cameron
Kimberly O
KO
Lefker
Bruce A
BA
Brown
Thomas A
TA
Thompson
David D
DD
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D015232:Dinoprostone / Q000819:agonists*; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000188:drug therapy*; D005453:Fluorescence; D017102:Fracture Healing / Q000187:drug effects*; D007267:Injections; D008297:Male; D015394:Molecular Structure; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013379:Substrate Specificity
C475539:CP533536; C545644:PTGER2 protein, human; C545646:Ptger2 protein, rat; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015232:Dinoprostone