Bone Regenerative Strategies Targeting the Notch Pathway
Dr. Steven Goudy is the Director of Pediatric Otolaryngology at Emory University where he has a laboratory focused on craniofacial bone development and regeneration. Working closely with Dr. Shelly Abramowicz, Associate Professor of Oral Surgery at Emory, they focus on developing regenerative approaches to pediatric craniofacial bone loss using animal models.
Using in vitro and in vivo approaches, Drs. Goudy and Abramowicz are developing innovative approaches for drug and cell delivery, leveraging their collaborations with the Georgia Institute of Technology.
The current options for bone grafting in adults include autologous bone graft harvest, donated autogenous bone, and bone regeneration using growth factor delivery, primarily using Bone Morphogenetic Protein 2 (BMP2). Options for bone grafting in children are limited due to concerns about use of donor bone and lack of FDA approval of BMP2 use in children. The development of a regenerative strategy to replace and/or repair bone loss in children is critically needed to reduce cost and morbidity.
Delivery of Bone Morphogenetic Protein 2 (BMP2) using a collagen sponge has successfully regenerated bone in adults to treat facial bone loss and during cervical spine fusion. BMP2 is not FDA-approved for the treatment of children due to the off target effects of BMP2, including life-threatening swelling and inflammation. Delivery of growth factors and cells requires that the delivery vehicle has moderate term permanence, avoids significant host tissue inflammation, and is easily cleared from the host. Many investigators are pursuing multiple pathways to identify additional genes, growth factors and cells that can be targeted for bone regeneration.
This proposal focuses on the Notch signaling pathway as a potential target to regenerate bone without inducing significant inflammation. Our lab has demonstrated the requirement of Jagged1, a cell surface ligand in the Notch pathway, during craniofacial bone formation and we have created a mouse model of maxillary bone loss. Jagged1 is a cell surface ligand in the Notch gene family that is necessary in determining cell fate. Human mutation of JAGGED1 leads to Alagille syndrome, characterized by cardiac, and bony phenotypes. Taken together these findings indicate that Jagged1 plays an important role in bone development, and interruption of Jagged1 function is associated with obvious clinical manifestations of bony loss and targeted Jagged1-therapies may provide another therapeutic option for bone regeneration in children.
JAGGED1 stimulates cranial neural crest cell osteoblast commitment pathways and bone regeneration independent of canonical NOTCH signaling Archana Kamalakar 1, Jay M McKinney 2, Daniel Salinas Duron 3, Angelica M Amanso 4, Samir A Ballestas 5, Hicham Drissi 6, Nick J Willett 7, Pallavi Bhattaram 8, Andrés J García 9, Levi B Wood 10, Steven L Goudy 11 PMID: 32980561. DOI: 10.1016/j.bone.2020.115657. Full Text