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 5

Loss of NOTCH signaling in mature osteoblasts does not lead to fracture nonunion.

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Loss of NOTCH signaling in mature osteoblasts does not lead to fracture ...
(A) A real-time radiographic comparison of 2 representative nonstabilized tibia fractures from WT and RBPjκCol1 mutant mice at 0, 14, 28, and 42 dpf revealed normal fracture repair in RBPjκCol1 mutants. n = 7 mice per genotype. (B) Representative μCT images of fracture calluses from WT and RBPjκCol1 mutants at 42 dpf. n = 7 mice per genotype. *P < 0.05 compared with WT by 2-tailed, unpaired Student’s t test. Results are expressed as mean ± SD. (C) Reconstruction of μCT data revealed a similar amount of mineralized calluses between WT and RBPjκCol1 mutants at 42 dpf. (D) ABH/OG-stained callus sections from RBPjκCol1 mutants and controls at 42 dpf. Original magnification, ×2.5. (E and F) Histomorphometric analyses of ABH/OG-stained callus sections indicated no significant differences in bone and mesenchyme area between WT and RBPjκCol1 mutant fractures. n = 7 mice per genotype. *P < 0.05 compared with WT by 2-tailed, unpaired Student’s t test. Results are expressed as mean ± SD.