NOTCH signaling in skeletal progenitors is critical for fracture repair
Cuicui Wang, … , Hani A. Awad, Matthew J. Hilton
Cuicui Wang, … , Hani A. Awad, Matthew J. Hilton
Published March 7, 2016
Citation Information: J Clin Invest. 2016;126(4):1471-1481. https://doi.org/10.1172/JCI80672.
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Research Article Bone Biology

NOTCH signaling in skeletal progenitors is critical for fracture repair

Abstract

Fracture nonunions develop in 10%–20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH-deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity.

Authors

Cuicui Wang, Jason A. Inzana, Anthony J. Mirando, Yinshi Ren, Zhaoyang Liu, Jie Shen, Regis J. O’Keefe, Hani A. Awad, Matthew J. Hilton

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Figure 1

Loss of NOTCH signaling in MSCs results in fracture nonunion.

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Loss of NOTCH signaling in MSCs results in fracture nonunion. (A) A real...
(A) A real-time radiographic comparison of 2 representative nonstabilized tibia fractures from WT and RBPjκPrx1 mutant mice at 0, 14, 28, and 42 dpf revealed persistent fracture lines (yellow arrows) at 42 dpf, suggesting an established fracture nonunion in RBPjκPrx1 mutants. n = 12 mice per genotype per time point. (B) μCT analyses of 14-, 28-, and 42-day-old WT and RBPjκPrx1 mutant fractures revealed substantial periosteal external callus formation by 14 dpf and beyond, but apparent radiolucent space (yellow arrows) between broken cortices at 42 dpf in RBPjκPrx1 mutants. n = 7 mice per genotype per time point. (C) Reconstruction of μCT data reflected the normal and robust periosteal response in RBPjκPrx1 mutants; however, the new bone remodeling was delayed in these animals. n = 7 mice per genotype per time point. *P < 0.05 compared with WT by 2-way ANOVA followed by Dunnett’s post hoc test. Results are expressed as mean ± SD.