Karl Jepsen, PhD

Research

1. Overview: The primary objective of my research program is to understand how complex physiological systems like bone establish function during growth and maintain function during aging. Having a better understanding of how complex systems work will benefit efforts to reduce skeletal fracture risk by identifying the genetic and environmental factors that impair (or promote) specific components of the functional adaptation process and that compromise (or improve) fracture resistance. 2. Advances: The skeletal system, like many physiological systems, establishes function by adapting to genetic and/or environmental perturbations. My research laboratory significantly advanced our understanding of this functional adaptation process by showing that the skeletal system compensates for the natural variation in robustness (a measure of bone width normalized to bone length) by simultaneously coordinating multiple morphological and tissue-quality traits. This coordination occurs during growth and results in each person acquiring a set of traits that is specifically adapted to their genetic background and life history. When viewed at the population level, this functional adaptation process results in a situation where variable compensatory traits are superimposed on the natural variation in skeletal robustness. This situation poses significant scientific challenges for identifying the biological factors regulating the functional adaptation process, as well as translational-challenges for identifying traits that have practical clinical value as advanced diagnostic measures of future fracture risk. We identified a pattern in the way individuals coordinate their traits. This pattern or network of trait interactions has experimental value in that genetic factors regulating each component of the network can be teased out and studied. The network also has tremendous clinical value because it means we can estimate a person's fracture risk and provide insight into potential therapies by first evaluating their particular set of acquired traits and determining how their trait set relates to bone strength and fracture resistance. Evaluating acquired trait sets provides a more flexible, personalized approach to identifying novel biomechanical and biological pathways contributing to bone fragility. 3. Basic Science Research Program: I have two RO1 grants that utilize Recombinant Inbred and Chromosome Substitution mouse strains to study how functional interactions among traits mature during growth and how this process defines adult bone stiffness, strength, and toughness. One grant focuses on the functional interactions among morphological and tissue-quality traits in the femoral diaphysis. The second grant focuses on functional interactions among morphological and tissue-quality traits in the vertebral body. The vertebral body is a more complex structure including a larger number of interactions among cortical and trabecular traits, and thus presents its own unique scientific challenges. 4. Translational Research Program: Much of the research conducted using inbred mouse strains, and many of the concepts learned from the mouse, have been successfully translated to the human skeleton. One important question that we addressed and answered is 'how effective is this adaptive process at establishing function across a population?' We recently identified an intrinsic "flaw" in the functional adaptation process of human bone that contributes to increased fracture susceptibility in a healthy, young adult population. Using a collection of pQCT images from over 1000 men and women from three countries (US, UK, Israel), we found the skeletal system was inherently limited in its ability to fully compensate the natural variation in bone size (robustness), leaving a predictable segment of the population at a functional deficit. This functional inequivalence was not problematic for daily load conditions, but increased fracture risk under extreme loading conditions. We propose to apply these methods to the aging population because it is expected that starting the aging process with a functional deficit will increase fracture risk earlier in life. Human diaphyseal bone shows a pattern of interactions among morphological and tissue-quality traits that is similar to what was observed in the mouse femur. Identifying patterns in the way traits covary across a population has tremendous clinical value for predicting an individuals skeletal strength and fracture risk, for predicting an individuals adaptive response to age-related bone loss, for investigating the biological basis of functionality, for identifying genetic and environmental factors that promote or impair the development and maintenance of function. 

Jepsen Laboratory