Anabolic actions of Notch on mature bone.
Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.
['Liu|Peng|P|', 'Ping|Yilin|Y|', 'Ma|Meng|M|', 'Zhang|Demao|D|', 'Liu|Connie|C|', 'Zaidi|Samir|S|', 'Gao|Song|S|', 'Ji|Yaoting|Y|', 'Lou|Feng|F|', 'Yu|Fanyuan|F|', 'Lu|Ping|P|', 'Stachnik|Agnes|A|', 'Bai|Mingru|M|', 'Wei|Chengguo|C|', 'Zhang|Liaoran|L|', 'Wang|Ke|K|', 'Chen|Rong|R|', 'New|Maria I|MI|', 'Rowe|David W|DW|', 'Yuen|Tony|T|', 'Sun|Li|L|', 'Zaidi|Mone|M|']
D000818:Animals D001854:Bone Marrow Cells D001842:Bone and Bones D002113:Calcification, Physiologic D002478:Cells, Cultured D005260:Female D049452:Green Fluorescent Proteins D000072100:Jagged-1 Protein D008297:Male D008822:Mice, Transgenic D010006:Osteoblasts D010012:Osteogenesis D053764:Presenilin-1 D051880:Receptors, Notch D017154:Stromal Cells D055114:X-Ray Microtomography
aging osteoporosis skeletal mineralization therapeutic target