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 rely on 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 in male mice without causing adverse effects in other organs, which are known to rely on intact Notch signaling. Due to lower bone surface and thereby reduced retention of Dll4((E12)), the same approach failed to promote osteogenesis in female and ovariectomized mice but strongly enhanced trabecular bone formation in combination with parathyroid hormone. Single cell analysis of stromal cells indicates that Dll4((E12)) primarily acts on MSCs and has comparably minor effects on osteoblasts, endothelial cells, or chondrocytes. We propose that activation of Notch signaling by bone-targeted fusion proteins might be therapeutically useful and can avoid detrimental effects in Notch-dependent processes in other organs.

Automated summary

This study investigates whether treatment with secreted Notch ligand proteins can enhance osteogenesis in adult mice. The findings reveal that bone-targeted Delta-like 4 can induce bone formation in male mice without adverse effects in other organs. However, it fails to promote osteogenesis in female mice and ovariectomized mice, but significantly enhances trabecular bone formation when combined with parathyroid hormone. Single cell analysis indicates that Delta-like 4 primarily acts on MSCs with minor effects on other cell types. Therefore, activation of Notch signaling through bone-targeted fusion proteins could be therapeutically useful and avoid detrimental effects in other organs.