Modulation of Notch1 signaling regulates bone fracture healing
| Autor: | Kurt D. Hankenson, Brya G. Matthews, Sanja Novak, Emilie Roeder, Douglas J. Adams, Benjamin P. Sinder, Danka Grčević, Chris Siebel, Ivo Kalajzic |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0206 medical engineering Notch signaling pathway 02 engineering and technology Bone healing Article 03 medical and health sciences Mice 0302 clinical medicine Osteoclast medicine Animals Orthopedics and Sports Medicine Progenitor cell Receptor Notch1 Notch signaling alpha-smooth muscle actin bone fracture inducible Cre osteoblast differentiation periosteal progenitors 030203 arthritis & rheumatology Fracture Healing Chemistry Cartilage Mesenchymal stem cell Mesenchymal Stem Cells Bone fracture medicine.disease 020601 biomedical engineering Cell biology medicine.anatomical_structure Callus Female |
| Zdroj: | J Orthop Res |
| ISSN: | 1554-527X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text