Mechanism of LRP5 and serotonin-mediated bone remodeling

Abstract

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.