Interplay between Notch signaling and parathyroid hormone enhances anabolic bone formation
Osteoporosis is a debilitating disease characterized by strongly diminished bone mass and increased fracture risk, affecting large parts of the elderly population. Intermittent parathyroid hormone (PTH) is an anabolic treatment used in severe osteoporosis but has several limitations. Therefore, it is critical to better understand the underlying mechanisms mediating the PTH response in bone. Here, we show that PTH increases the mass and strength of long bones by expanding osteoprogenitor cells but also through alterations in the vasculature, effects that involve increased Notch signaling. Unexpectedly, endothelial cell-specific inactivation of the Notch ligand Delta-like 4 (Dll4) enhances PTH-induced osteogenesis but alters the patterning of newly formed trabeculae. Conversely, a strategy exploiting soluble, bone-targeted Notch activation enhances the effect of PTH even with lower doses of the hormone. Our findings establish that endothelial-to-mesenchymal Notch signaling controls the spatial pattern of trabecular bone formation and is critical for the anabolic action of PTH.