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

Anna Li; Xuechun Xia; James Yeh; Huiyi Kua; Huijuan Liu; Yuji Mishina; Aijun Hao; Baojie Li

doi:10.1371/journal.pone.0113785

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

PLoS One. 2014 Dec 3;9(12):e113785. doi: 10.1371/journal.pone.0113785. eCollection 2014.

Authors

Anna Li¹, Xuechun Xia², James Yeh², Huiyi Kua³, Huijuan Liu², Yuji Mishina⁴, Aijun Hao⁵, Baojie Li²

Affiliations

¹ 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.
² The Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
³ The Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore 138632, Singapore.
⁴ Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America.
⁵ Department of Histology and Embryology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong, 250012 P.R. China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Bone Morphogenetic Protein 2 / metabolism*
Bone Morphogenetic Protein Receptors, Type I / deficiency
Bone Morphogenetic Protein Receptors, Type I / genetics
Cell Differentiation / drug effects*
Cell Movement / drug effects*
Cells, Cultured
Down-Regulation / drug effects
Mesenchymal Stem Cells / drug effects*
Mesenchymal Stem Cells / metabolism
Mice, Inbred C57BL
Mice, Knockout
Osteogenesis / genetics
Platelet-Derived Growth Factor / pharmacology*
Protein Binding
RNA Interference
Receptor, Platelet-Derived Growth Factor alpha / genetics
Receptor, Platelet-Derived Growth Factor alpha / metabolism*
Signal Transduction / drug effects
Smad Proteins / metabolism*
Smad1 Protein / metabolism
Smad5 Protein / metabolism
Smad8 Protein / metabolism

Substances

Bmp2 protein, mouse
Bone Morphogenetic Protein 2
Platelet-Derived Growth Factor
Smad Proteins
Smad1 Protein
Smad5 Protein
Smad8 Protein
platelet-derived growth factor A
Receptor, Platelet-Derived Growth Factor alpha
Bmpr1a protein, mouse
Bone Morphogenetic Protein Receptors, Type I

Grants and funding

The work was supported by grants from the Ministry of Science and Technology of China (The National Key Scientific Program (2012CB966901, to BL))(http://www.most.gov.cn/) and the National Natural Science Foundation of China (81130039, 31071229, and 81121001(http://www.nsfc.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.