Development of the skeletal elements in vertebrates requires precise control over cell growth and size. All long bones of vertebrates are formed via endochondral ossification where bone forms from chondrocyte precursors. During this process, chondrocytes undergo hypertrophy in order to elongate the developing bone. Recently, three distinct phases of hypertrophy were discovered in these chondrocytes and differences in the Insulin growth factor (IGF)-dependent third phase were found to be responsible for differences in bone lengths. These findings open several questions on bone development and repair as well as pathologies that result in shortened skeletal elements. How IGF signaling regulates chondrocyte hypertrophy remains poorly understood, specifically what the downstream targets are that mediate this process. Further, during fracture repair, chondrocytes enlarge more than that observed during development. The dynamics of chondrocyte hypertrophy in this context have not been investigated and it remains unclear if this truly recapitulates development or if alternative mechanisms are employed. Finally, multiple genetic disorders result in shortened long bones of the limbs. Despite an understanding of the genetic cause behind some of these disorders, the mechanisms that result in shortened bones is not known. Therefore, the objectives of this study are to examine IGF signaling in chondrocyte hypertrophy during development and fracture repair. Finally, this study will investigate chondrocyte hypertrophy dynamics in mouse models for skeletal diseases that result in shortened limbs. In order to test the following hypotheses: (1) Downstream transcriptional targets of the IGF signaling pathway mediate hypertrophy in chondrocytes. (2) Repair following bone fracture requires IGF dependent chondrocyte hypertrophy and (3) Genetic pathologies that result in shortened long bones lack specific phases of chondrocyte hypertrophy. I propose the following aims.
Specific Aim 1 : Determine the targets of IGF signaling that mediate chondrocyte hypertrophy.
Specific Aim 2 : Investigate the growth of hypertrophic chondrocytes and IGF signaling dependence in repairing bone.
Specific Aim 3 : Assess chondrocyte size and dynamics in mouse models of genetic disorders that result in shortened limbs. The successful completion of these experiments will generate a more complete understanding of IGF signaling and how it controls skeletal morphology. Further, findings from this study will broaden our knowledge of bone repair and regeneration as well as suggest potential therapeutic targets for developmental bone diseases.
Each year, approximately 6 million Americans will suffer a bone fracture and millions more are affected by genetic bone disorders. The skeletal system provides form and function while continuously retaining the ability to regenerate, yet the mechanisms that regulate bone formation during development and repair following fractures remain poorly understood. The experiments outlined in this proposal will focus on the molecular mechanisms that determine bone length during development, bone repair following fractures, and genetic disorders that result in shortened limbs.
