PROTECT · Preventing Bone Loss by Targeting Endothelial Cell-Tissue Crosstalk

During healthy aging but also in osteoporosis, a disease that affects more than 22% of European women beyond the age of 50, loss of mineralized bone is caused by a disbalance between bone formation and resorption. While blood vessels are abundant in the skeletal system and play essential roles, they are currently not considered in the context of anti-osteoporosis therapy. Moreover, apart from the role of sex hormones, we know too little about the impact of sex-specific regulators in physiological and disturbed bone homeostasis. Our recent work has provided fundamental insights into the organization of the bone vasculature in mouse, the heterogeneity and functional specialization of endothelial cells (ECs), and the changes during aging. Recent and unpublished research from my team has utilized single cell RNA sequencing in combination with advanced immunostaining and imaging to identify a novel EC subpopulation (termed type R for remodeling). Type R vessels are post-arterial capillaries found at sites of homeostatic and therapeutic bone turnover, mainly trabecular bone, and their activation in young mice can enhance osteogenesis. In aging mice type R vessel clusters emerge inside cortical bone at sites of bone loss. PROTECT will systemically characterize the function of ECs and, in particular, type R capillaries in healthy homeostasis and during bone loss. This will involve the generation of new mouse lines for intersectional genetics and the characterization of critical molecular regulators. We will also characterize sex-specific and age-related factors controlling bone homeostasis and employ approaches to translate our findings into the human system. Preclinical experiments in mice will establish whether ECs and type R capillaries are involved in the response to therapies aiming at osteoblasts or osteoclasts. PROTECT will generate the conceptual basis for future approaches utilizing endothelial cells for the prevention of bone loss and anti-osteoporotic therapy.