title: Mechanical stretch suppresses BMP4 induction of stem cell adipogenesis via upregulating ERK but not through downregulating Smad or p38.
abstract: Bone morphogenetic proteins (BMPs) are also implicated in the commitment of mesenchymal stem cells (MSCs) toward adipocytes. We tested that stretching of cells may downregulate BMP4 induction of MSC adipogenesis. C3H10T1/2 MSCs were pretreated with BMP4 and induced to differentiate to adipocytes using adipogenic hormonal inducers. To test the stretch effect on BMP4 function, cells were exposed to cyclic tensile stretch (10% strain, 0.25Hz, 120min/day) during the BMP4 pretreatment period. BMP4 induced MSC adipocytic commitment. Stretching during the BMP4 exposure could suppress BMP4 induction of MSC adipogenesis, as assessed by downregulated adipogenic transcription factors (PPARγ, C/EBPα, aP2) and decreased lipid accumulation. BMP4 signaled through Smad1/5/8 and p38MAPK, whereas cell stretch did not affect BMP4-induced activation in Smad or p38. On the other hand, cell stretch triggered significant ERK1/2 phosphorylation relative to BMP4 treatment alone cells. Further, stretch suppression of BMP4-induced MSC adipogenesis was significantly deteriorated if cells were stretched with ERK blocked by PD98059. Combined, these suggest that cell stretch suppresses the BMP4 induction of MSC adipogenesis potentially via upregulating ERK but not through the downregulation of Smad or p38. Our data on inhibiting MSC adipogenesis will be of significant interest for obesity and developmental mechanobiology studies.
authors.affiliation: Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
authors.forename: Jeong Soon
authors.initials: JS
authors.lastname: Lee
authors.forename: Ligyeom
authors.initials: L
authors.lastname: Ha
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Jung Yul
authors.initials: JY
authors.lastname: Lim
mesh_terms: D050156:Adipogenesis; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis*; D002460:Cell Line; D015536:Down-Regulation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism*; D013314:Stress, Mechanical; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D051785:Smad Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases