Intermittent activation of notch signaling promotes bone formation.

Stimulatory and inhibitory effects of Notch signaling pathway on osteogenesis were both widely reported, questioning the effectiveness of small molecules targeting the Notch pathway for prevention or treatment of bone loss diseases. Here we showed that Notch signaling is activated in osteocytes embedded within the mineralized matrix and in late stages of bone marrow mesenchymal cell osteogenic cultures. Inhibition of Notch signaling markedly reduced mineralization activities of bone marrow mesenchymal cells and inhibited expressions of mineralization-associated genes when Notch ligand Jagged1 was conditionally deleted, confirming the essential roles of Notch signaling in mineralization stages of osteoblast differentiation. Moreover, intermittent activation of Notch signaling showed significant increases of bone formation in mice, rats and ovariectomized rats. A two-phase action model of Notch signaling in osteogenesis is proposed, where activation of Notch signaling in early stages of osteoblast differentiation results in proliferation of immature preosteoblast lineage cells and activation in late stages promotes differentiation of osteoblasts into osteocytes. Moreover, valproic acid is a strong activator of Notch signaling, and yearly administration of valproic acid daily showed little side effects, indicating that long term and intermittent activation of Notch signaling will be a safe and ideal way to promote anabolic bone formation for treatment of osteoporosis. Therefore, Notch signaling pathway is a good therapeutic target for bone loss diseases, and valproic acid, resveratrol and other Notch activators are promising therapeutic molecules for promoting anabolic bone formation when administered intermittently.