title: MAPK signaling has stage-dependent osteogenic effects on human adipose-derived stem cells in vitro.
abstract: The use of pro-osteogenic growth factors, such as BMP2, in human adipose-derived stem cell (ASC) osteogenesis is well described. Because these growth factors work via signal transduction pathways, such as the mitogen-activated protein kinase (MAPK) cascade, a study of the relationship between MAPK signaling and ASC osteogenesis was conducted.
  
  
  
  ERK, JNK, and p38MAPK activation were measured in ASCs osteo-induced using either dexamethasone or vitamin D3 and correlated with mineralization. Activation and mineralization were also measured without dexamethasone or using the glucocorticoid, cortisone. The expression of the MAPK phosphatase, MKP1, and its relationship to mineralization was also assessed. The effect of decreasing MAPK activation on mineralization through the use of exogenous inhibitors was examined along with siRNA-knockdown and adenoviral overexpression of ERK1/2. Finally, the effect of ERK1/2 overexpression on ASCs induced on PLGA scaffolds was assessed.
  
  
  
  ASC mineralization in dexamethasone or vitamin D3-induced ASCs correlated with both increased ERK1/2 and JNK1/2 activation. ASCs induced without dexamethasone also mineralized, with JNK1/2 signaling possibly mediating this event. No link between cortisone induction and MAPK signaling could be ascertained. ASCs treated with ERK, JNK, or p38MAPK inhibitors showed decreased osteogenic gene expression and diminished mineralization. Mineralization levels were also affected by viruses designed to inhibit or augment ERK1/2 expression and activity. Finally, ASC mineralization appeared to be a balance between the MAPK kinase activity and MKP1.
  
  
  
  It is likely that MAPK signaling plays a significant role in ASC osteogenesis, affecting differentiation in kinase- and stage-specific manners.
authors.affiliation: a Regenerative Bioengineering and Repair Laboratory, Department of Surgery , David Geffen School of Medicine at UCLA, University of California , Los Angeles , CA , USA.|b Department of Bioengineering , Henry Samueli School of Engineering and Applied Sciences, University of California , Los Angeles , CA , USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Tsang
authors.affiliation: b Department of Bioengineering , Henry Samueli School of Engineering and Applied Sciences, University of California , Los Angeles , CA , USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.affiliation: a Regenerative Bioengineering and Repair Laboratory, Department of Surgery , David Geffen School of Medicine at UCLA, University of California , Los Angeles , CA , USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Zuk
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D010012:Osteogenesis; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: Adipose-derived stem cells; ERK1/2; JNK1/2; MAPK signaling; osteogenesis