Establishing JAGGED1-Based Approaches For Bone Regeneration
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Kaimari, Sundus
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Abstract
Craniofacial bone loss is a widespread issue due to the high incidence of traumatic and congenital injuries in these areas. Current bone regenerative strategies involve the use of autografts and allografts, however they come with drawbacks, such as donor-site morbidity and graft rejection. For example, bone morphogenetic protein-2 (BMP2) has been found to accelerate bone regeneration, but treatment with BMP2 can lead to ectopic bone hypertrophy and uncontrolled inflammation. Our research focuses on JAGGED1 (JAG1) as a potential therapy for craniofacial bone loss in pediatric patients. Recent work from our lab demonstrated the ability of JAG1 to promote differentiation and mineralization of pediatric human fibular bone derived osteoblast-like (HBO) cells in vitro and bone regeneration in a murine critical-size defect model. Additionally, we identified p70 S6K, the NOTCH non-canonical gene, as a key target gene for bone formation. In this study, we aimed to develop a drug delivery method for JAG1 and identify activators of p70 S6K phosphorylation as alternative osteo-inductive therapies. To present JAG1 in the appropriate configuration, we immobilized JAG1 to a PEG 4-MAL hydrogel by modifying it with a thiol-terminated PEG linker. The resulting hydrogel induced increased mineralization of HBO cells compared to its unmodified control. We also developed a high throughput TR-FRET-based assay to pinpoint downstream targets of JAG1-NOTCH non-canonical signaling. The assay identified 15 out of 2,036 FDA-approved compounds as inducers of p70 S6K phosphorylation. Validation studies demonstrated that these compounds induced p70 S6K phosphorylation and mineralization in HBO cells.
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2024-04-29
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