Fracture Repair

Fracture healing is a complex process that typically occurs efficiently, but is compromised in certain conditions, including aging.  The repair process begins with inflammation and hematoma formation followed by chondrogenesis of mesenchymal stem cells and formation of a soft cartilage callus.  Through both endochondral and intramembranous bone formation, the soft callus is replaced by mineralized bone.  This bone is ultimately remodeled to reestablish the original cortical bone structure.  Our lab uses mouse femur and tibia fracture models to study, in vivo, the signaling pathways required for efficient fracture healing.  We have established, for example, that the Cox-2/PGE2 signaling pathway is critical for normal bone repair.  PGE2, the major downstream product of Cox-2, is a secreted factor that binds four different G protein-coupled receptors, EP1, EP2, EP3, and EP4. Interestingly, Cox-2-/- mice exhibit delayed fracture healing, while EP1-/- mice exhibit accelerated fracture healing.  Treatment of Cox-2-/- mice with an EP4 agonist, however, rescues the impaired fracture healing.  These findings suggest that while EP4 may play a positive role in PGE2-mediated fracture repair, EP1 likely plays an inhibitory role.  Currently, we are using genetic mouse models and in vitro cell culture assays to define which cell types and which receptors are essential for normal fracture repair downstream of Cox-2.  Additionally, we are exploring the ability of PTH as well as the use of small molecule agonists or inhibitors of the Cox-2/PGE2 signaling pathway to improve fracture healing in cases of inefficient repair.

Contact

Regis J. O'Keefe, M.D., Ph.D.
University of Rochester
601 Elmwood Ave., Box 665
Rochester, NY 14642
Office: SMD 1-8535
(585) 275-5321
Regis_OKeefe@URMC.
Rochester.edu