Show simple item record

Neurofibromin Regulated Signaling Pathways in Endochondral Ossification

dc.creatorKarolak, Matthew Ross
dc.description.abstractNeurofibromatosis type 1 (NF1) is the most common autosomal dominant genetic disorder occurring in 1 of every 3500 live births. NF1 is caused by loss-of-function mutations in NF1, the gene encoding the Ras-GAP neurofibromin. Forty percent of NF1 patients will develop orthopedic complications which often includes unilateral bowing of the extremities, fracture, and subsequent fracture healing deficits (pseudarthrosis). Because the molecular and cellular aspects mechanisms of fracture healing largely recapitulate the processes of bone development, the goal of this dissertation is to characterize the function of neurofibromin in growth plate chondrocytes and the signaling pathways it regulates during endochondral ossification. Using conditional mouse knockout models of NF1, we found that neurofibromin regulates growth plate chondrocyte proliferation, hypertrophic maturation, and matrix catabolism at the osteochondral border. Furthermore, we found that neurofibromin in prehypertrophic chondrocytes likely attenuates FGFR1 and FGFR3 signaling to inhibit chondrocyte proliferation, and neurofibromin in hypertrophic chondrocytes attenuates FGFR1 signaling to inhibit matrix catabolism as the osteochondral border. Finally, in a series of pharmacological proof-of-principle experiments, we identified C-type natriuretic peptide and the pan-FGFR inhibitor BGJ-398 as potential therapeutic agents for the treatment of NF1 pseudarthroses via their action on Nf1-/- chondrocytes. Further investigation of these agents in NF1 fracture healing models is warranted.
dc.subjectNeurofibromatosis Type 1
dc.subjectGrowth Plate
dc.subjectFracture Healing
dc.titleNeurofibromin Regulated Signaling Pathways in Endochondral Ossification
dc.contributor.committeeMemberEla Knapik
dc.contributor.committeeMemberXiangli Yang
dc.contributor.committeeMemberFlorent Elefteriou
dc.contributor.committeeMemberJonathan Schoenecker
dc.type.materialtext University
dc.contributor.committeeChairJoey Barnett

Files in this item


This item appears in the following Collection(s)

Show simple item record