title: PDGF-AA promotes osteogenic differentiation and migration of mesenchymal stem cell by down-regulating PDGFRα and derepressing BMP-Smad1/5/8 signaling.
abstract: 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.
authors.affiliation: Department of Histology and Embryology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong, 250012 P.R. China; The Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Anna
authors.initials: A
authors.lastname: Li
authors.affiliation: The Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xuechun
authors.initials: X
authors.lastname: Xia
authors.affiliation: The Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: James
authors.initials: J
authors.lastname: Yeh
authors.affiliation: The Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore 138632, Singapore.
authors.forename: Huiyi
authors.initials: H
authors.lastname: Kua
authors.affiliation: The Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Histology and Embryology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong, 250012 P.R. China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Hao
authors.affiliation: The Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010012:Osteogenesis / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011485:Protein Binding; D034622:RNA Interference; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D010982:Platelet-Derived Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I