Mechanism of LRP5 and serotonin-mediated bone remodeling

The process of bone formation is essential to life of all vertebrates. Our understanding of the molecular mechanisms involved in this process are still limited. Osteoporosis is a common and often crippling human disease characterized by decreased de novo bone formation by osteoblasts. The incidence of this disease is growing with the aging of the general population. One condition favoring an extreme form of osteoprosis is due to loss of function mutations in the LRP5 gene. This results in a decrease in osteoblast function leading to low bone mass. Recent study in Gerard Karsenty’s laboratory showed that LRP5 promotes osteoblast function by suppressing serotonin biosynthesis in enterochromaffin gut cells. Consistently, decrease in serum serotonin levels results in increased proliferation of osteoblasts and accounts for a protective mechanism against osteoporosis. This has been verified in both mice and humans in a rare condition called the high bone mass syndrome. These exiting findings opened up novel research avenues. The aim of my proposal is to further characterize the interplay between enterochromaffin cells and osteoblasts and to identify and characterize the molecular pathways involved in regulation of serotonin by LRP5. To achieve these goals, I plan to use various biochemical, cell biology and mouse genetics approaches. I expect these studies to contribute to a better understanding of molecular pathways crucially involved in formation of bone both during normal and disease development.