Bone reloaded

Osteoporosis is a major socioeconomic health burden with about 200 million patients worldwide. Imbalances in bone remodeling and uncoupled remodeling are key mechanisms in the pathogenesis of osteoporosis. Bone remodeling is a cyclic renewal mechanism in which bone formation follows bone resorption in the same skeletal site. Under normal conditions in healthy adults, the quantum of bone formed matches the amount of bone resorbed, i.e., resorption and formation are coupled and the remodeling balance is zero. Most of the work attempting to elucidate the molecular mechanisms underlying the regulation of bone remodeling has been done in mice, a species lacking remodeling in cortical bone. Here, we aim to overcome the limitations of mouse models by focusing on sheep, a species characterized by bone remodeling similar to humans.

We will employ a novel, reversible stress-shielding model in the shinbone of sheep to test the hypothesis that all steps of bone remodeling, including bone resorption, coupling, and bone formation are orchestrated by biomechanical signals. By harnessing the power of newly developed spatial biology technologies in bone in combination with biomechanical modeling and computational systems biology, we will further explore the nature of the biochemical signals and the pathways involved in the coupling mechanism and in the regulation of bone remodeling. Improved knowledge of the cellular and molecular mechanisms controlling bone remodeling may eventually lead to new possibilities for the prevention, diagnosis, and treatment of osteoporosis.