Induction of osteogenesis by bone-targeted Notch activation

Declining bone mass is associated with aging and osteoporosis, a disease characterized by progressive weakening of the skeleton and increased fracture incidence. Growth and lifelong homeostasis of bone involve interactions between different cell types including vascular cells and mesenchymal stromal cells (MSCs). As these interactions involve Notch signaling, we have explored whether treatment with secreted Notch ligand proteins can enhance osteogenesis in adult mice. We show that a bone-targeting, high affinity version of the ligand Delta-like 4 (termed Dll4(E12)) induces bone formation without causing adverse effects in other organs, which are known to rely on intact Notch signaling interactions. Single cell analysis of stromal cells indicates that Dll4(E12) primarily acts via bone marrow MSCs and has comparably minor effects on osteoblast lineage cells, endothelial cells or chondrocytes. Based on this example, we propose that bone-targeted fusion proteins might be therapeutically useful and can avoid detrimental effects caused by systemic administration. Bone marrow stromal single cell RNA sequencing of 11-week old wild type (WT) and Dll4(E12) treated mice