PDGF-AA promotes osteogenic differentiation and migration of mesenchymal stem cell by down-regulating PDGFRα and derepressing BMP-Smad1/5/8 signaling

• Published in: PloS one 2014-12, Vol.9 (12), p.e113785-e113785
• Main Authors: Li, Anna, Xia, Xuechun, Yeh, James, Kua, Huiyi, Liu, Huijuan, Mishina, Yuji, Hao, Aijun, Li, Baojie
• Format: Article
• Language: English
• Subjects: Animals; Biocompatibility; Biology and Life Sciences; Blotting, Western; Bone healing; Bone marrow; Bone Morphogenetic Protein 2 - metabolism; Bone Morphogenetic Protein Receptors, Type I - deficiency; Bone Morphogenetic Protein Receptors, Type I - genetics; Bone morphogenetic proteins; Cbfa-1 protein; Cell adhesion & migration; Cell Differentiation - drug effects; Cell growth; Cell migration; Cell Movement - drug effects; Cells, Cultured; Complex formation; Cytokines; Differentiation (biology); Down-Regulation - drug effects; Education; Embryogenesis; Embryology; Embryonic growth stage; Fractures; Genetics; Growth factors; Histology; Homeostasis; Kinases; Laboratory animals; Mesenchymal stem cells; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchyme; Mice, Inbred C57BL; Mice, Knockout; Osteogenesis - genetics; Platelet-derived growth factor; Platelet-Derived Growth Factor - pharmacology; Protein Binding; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Regulators; Research and Analysis Methods; RNA Interference; Signal transduction; Signal Transduction - drug effects; Signaling; Smad Proteins - metabolism; Smad1 Protein - metabolism; Smad5 Protein - metabolism; Smad8 Protein - metabolism; Stem cells; Wound healing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113785

Platelet-derived growth factors (PDGFs) play important roles in skeletal development and bone fracture healing, yet how PDGFs execute their functions remains incompletely understood. Here we show that PDGF-AA, but not -AB or -BB, could activate the BMP-Smad1/5/8 pathway in mesenchymal stem cells (MSCs), which requires BMPRIA as well as PDGFRα. PDGF-AA promotes MSC osteogenic differentiation through the BMP-Smad1/5/8-Runx2/Osx axis and MSC migration via the BMP-Smad1/5/8-Twist1/Atf4 axis. Mechanistic studies show that PDGF-AA activates BMP-Smad1/5/8 signaling by feedback down-regulating PDGFRα, which frees BMPRI and allows for BMPRI-BMPRII complex formation to activate smad1/5/8, using BMP molecules in the microenvironment. This study unravels a physical and functional interaction between PDGFRα and BMPRI, which plays an important role in MSC differentiation and migration, and establishes a link between PDGF-AA and BMPs pathways, two essential regulators of embryonic development and tissue homeostasis.