Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration

Previous studies have demonstrated that Notch signaling regulates endochondral and intramembranous bone formation by controlling cell proliferation and differentiation. Notch signaling has also been shown to regulate healing in a variety of tissues. The objective of this study was to characterize and compare activation of the Notch signaling pathway during endochondral and intramembranous bone healing using tibial fracture and calvarial defect injury models, respectively. Bilateral tibial fractures or bilateral 1.5?mm diameter calvarial defects were created in mice, and tissues were harvested at 0, 5, 10, and 20 days post-fracture. Gene expression of Notch signaling components was upregulated during both tibial fracture and calvarial defect healing, with expression generally higher during tibial fracture healing. The most highly expressed ligand and receptor during healing, Jag1 and Notch2 (specifically the activated receptor, known as NICD2), were similarly localized in mesenchymal cells during both modes of healing, with expression decreasing during chondrogenesis, but remaining present in osteoblasts at all stages of maturity. Results suggest that in addition to embryological bone development, Notch signaling regulates both endochondral and intramembranous bone healing. (C) 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:296303, 2012