Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects

Each year, 33% of US citizens suffer from a musculoskeletal condition that requires medical intervention, with direct medical costs approaching $1 trillion USD per year. Despite the ubiquity of skeletal dysfunction, there are currently limited safe and efficacious bone growth factors in clinical use. Notch is a cell–cell communication pathway that regulates self-renewal and differentiation within the mesenchymal/osteoblast lineage. The principal Notch ligand in bone, Jagged-1, is a potent osteoinductive protein that positively regulates post-traumatic bone healing in animals. This report describes the temporal regulation of Notch during intramembranous bone formation using marrow ablation as a model system and demonstrates decreased bone formation following disruption of Jagged-1 in mesenchymal progenitor cells. Notch gain-of-function using recombinant Jagged-1 protein on collagen scaffolds promotes healing of craniofacial (calvarial) and appendicular (femoral) surgical defects in both mice and rats. Localized delivery of Jagged-1 promotes bone apposition and defect healing, while avoiding the diffuse bone hypertrophy characteristic of the clinically problematic bone morphogenetic proteins. It is concluded that Jagged-1 is a bone-anabolic agent with therapeutic potential for regenerating traumatic or congenital bone defects.
Jagged-1 helps heal fractures faster Localized and temporary delivery of the protein Jagged-1 promotes bone regeneration in rodents. Despite the large incidence of bone injuries in humans, current therapies to stimulate bone growth can have serious side effects. Kurt Hankenson at the University of Michigan, US, and colleagues have been investigating ways to stimulate Notch receptors, key regulators of bone formation during development. They found that levels of the Notch receptor’s binding partner Jagged-1 were significantly increased after bone injury and that disruption of Jagged-1 prevented bone healing in mice. Bone repair in both mice and rats was significantly improved following delivery of Jagged-1 on a collagen scaffold to the site of injury compared with controls. These findings could pave the way for safer and more efficient therapies to repair bone damage due to injury or inherited bone diseases.