An EP2 receptor-selective prostaglandin E₂agonist induces bone healing

Abstract

The morbidity and mortality associated with impaired͞delayed fracture healing remain high. Our objective was to identify a small nonpeptidyl molecule with the ability to promote fracture healing and prevent malunions. Prostaglandin E2 (PGE2) causes significant increases in bone mass and bone strength when administered systemically or locally to the skeleton. However, due to side effects, PGE2 is an unacceptable therapeutic option for fracture healing. PGE2 mediates its tissue-specific pharmacological activity via four different G protein-coupled receptor subtypes, EP1, -2, -3, and -4. The anabolic action of PGE2 in bone has been linked to an elevated level of cAMP, thereby implicating the EP2 and͞or 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 PGE2, suggesting that the EP2 receptor subtype is a major contributor to PGE2'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.T he skeleton has the unique ability to repair and heal itself after injury (1, 2). This process is a cascade of synchronized events involving many systemic and local signaling molecules (3). However, in Ϸ10% of cases, fractured bones heal more slowly (malunion) or fail to heal (nonunion), requiring additional costly medical intervention to repair the fracture (4). These malunions and nonunions cause significant patient morbidity, significantly limiting quality of life and increasing healthcare costs. New therapies that could ensure rapid healing of fractures and bone defects would lessen the need for further medical intervention and greatly reduce the morbidity and loss of independence associated with immobilization.The discovery of bone morphogenetic proteins has increased our understanding of the cascade of events that takes place during fracture healing. Several clinical studies demonstrate the capability of these proteins to induce and facilitate this process (5-8). However, the cost effectiveness, degree of clinical benefit, and long-term safety of these therapies have not been fully elucidated. These issues prompted us to identify additional mechanisms and pathways involved in bone formation that could be modulated with a nonpeptidyl small molecule. Such a compound could be used as a therapy to promote fracture healing and prevent malunions. Prostaglandin E 2 (PGE 2 ) has been shown to have multiple biological effects in many tissues, including bone. PGE 2 causes significant increases in bone mass and bone strength when administered systemically or locally to the skeleton (9-11). However, due to side effects, including diarrhea, lethargy, and flushing, PGE 2 is an unacceptable therapeutic option for bone healing. PGE 2 binds to and elicits its pharmacological activity from four different cell surface receptor subtypes, EP1, -2, -3, and -4 (12-16). T...

Effects of selective prostaglandins E2 receptor agonists on cultured calvarial murine osteoblastic cells

“…Previous reports have demonstrated that EP2 selective agonists are anabolic in organ culture and in vivo (7,9,10). Yet we only observed small effects of EP2A in the present study.…”

“…Recent studies using animals with deletion of either the EP2 or EP4 receptors or using selective agonists for these receptors have suggested that both EP2 and EP4 can mediate anabolic responses to PGE 2 (4)(5)(6)(7)(8)(9)(10), although the EP1 receptor may also be involved (11). Activation of EP2 and EP4 receptors increases cAMP and can also induce COX-2, which can result in auto-amplification of PGE 2 signaling (12).…”

Effect of deletion of the prostaglandin EP2 receptor on the anabolic response to prostaglandin E2 and a selective EP2 receptor agonist

“…While EP4 activation may be more effective at increasing osteoblast differentiation, activators of the EP2 receptor may still prove useful clinically. A different selective EP2 receptor agonist has recently been shown to enhance healing of bone defects and increase bone formation when injected locally [13]. Moreover EP2 receptor activation may have the advantage, based on our previous studies in rat organ cultures [3], that it has relatively less stimulatory effect on bone resorption than EP4 activation.…”

The rational use of animal models in the evaluation of novel bone regenerative therapies

“…Tool for assessment and follow up of a long bone healing along the bone healing cascade expressed as a healing grade [12,13] and % of bone healed. The early phase of healing (grade 0-3) enables temporarily fracture stabilization and further endochondral bone formation, and is characterized by the recruitment of mesenchymal cells and successive chondrogenesis resulting in a soft callus formation [14].…”