Regulatory Analysis of Bone Morphogenetic Protein5 Expression in Fracture Healing

Stanford University, Stanford CA

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Over the course of a lifetime 1 in every 2 men and 1 in every 3 women will fracture at least one bone in their skeleton. This translates into about 5.6 million skeletal fractures a year. Strikingly, nearly 25% of these patients experience impaired fracture healing including malunion or nonunion. Our current understanding of the molecular regulation underlying fracture repair remains somewhat limited, preventing development of novel therapeutic strategies to enhance fracture repair. Important characteristics of such novel treatments include shortening the healing time and preventing impaired healing. One method to gain more insight is to compare gene regulation in embryonic bone development with bone injury repair. Genes involved in both processes are likely targets for such novel therapeutics. Bone morphogenetic proteins (Bmps) are key signals used by vertebrates to control both embryonic bone formation and repair of bone fractures. Bmps are very interesting because of their ability to induce formation of ectopic bone and cartilage when injected into animals subcutaneously. One member, Bmp5, is required for both normal skeletal development and fracture repair. Therefore, Bmp5 can be examined to determine if the same regulatory mechanisms used to generate tissue during embryonic development are being reactivated to regenerate tissue during healing. However, unlike embryologic patterning, fractures occur at unpredictable times and locations and therefore may be controlled by very different kinds of regulatory elements. The specific aims designed to elucidate the mechanisms of Bmp5 reactivation following fracture and compare them to embryonic Bmp5 expression are to: 1) Characterize endogenous Bmp5 expression during normal rib fracture healing using in situ hybridization. 2) Map the cis-acting control elements responsible for Bmp5 induction following rib fracture by surveying transgenic lines spanning the Bmp5 locus. Compare fracture repair elements to embryonic enhancers to determine if the fracture repair response is local reactivation of the skeletal developmental genetic program. 3) Determine whether there is a general fracture response element or if unique fracture repair sequences control BMP expression following injury at different locations in the skeleton. The long-term goal is to elucidate the location and logic of regulatory sequences that cause Bmp5 to turn on at specific anatomic sites of bone injury as a necessary prerequisite to the development of new therapeutic models to enhance fracture repair, address clinical problems relating to bone loss and make advances in bony tissue engineering. [unreadable] [unreadable] [unreadable]