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Modulation of Notch1 signaling regulates bone fracture healing
Author(s) -
Novak Sanja,
Roeder Emilie,
Sinder Benjamin P.,
Adams Douglas J.,
Siebel Chris W.,
Grcevic Danka,
Hankenson Kurt D.,
Matthews Brya G.,
Kalajzic Ivo
Publication year - 2020
Publication title -
journal of orthopaedic research®
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.24650
Subject(s) - notch signaling pathway , bone healing , microbiology and biotechnology , osteoclast , chemistry , signal transduction , cartilage , progenitor cell , callus , stem cell , anatomy , biology , in vitro , biochemistry , botany
Fracture healing involves interactions of different cell types, driven by various growth factors, and signaling cascades. Periosteal mesenchymal progenitor cells give rise to the majority of osteoblasts and chondrocytes in a fracture callus. Notch signaling has emerged as an important regulator of skeletal cell proliferation and differentiation. We investigated the effects of Notch signaling during the fracture healing process. Increased Notch signaling in osteochondroprogenitor cells driven by overexpression of Notch1 intracellular domain (NICD1) (αSMACreERT2 mice crossed with Rosa‐NICD1) during fracture resulted in less cartilage, more mineralized callus tissue, and stronger and stiffer bones after 3 weeks. Periosteal cells overexpressing NICD1 showed increased proliferation and migration in vitro. In vivo data confirmed that increased Notch1 signaling caused expansion of alpha‐smooth muscle actin (αSMA)‐positive cells and their progeny including αSMA‐derived osteoblasts in the callus without affecting osteoclast numbers. In contrast, anti‐NRR1 antibody treatment to inhibit Notch1 signaling resulted in increased callus cartilage area, reduced callus bone mass, and reduced biomechanical strength. Our study shows a positive effect of induced Notch1 signaling on the fracture healing process, suggesting that stimulating the Notch pathway could be beneficial for fracture repair.