title: Activation of the ERK pathway in osteoblastic cells, role of gremlin and BMP-2.
abstract: Gremlin is a glycoprotein that binds and antagonizes the actions of bone morphogenetic proteins (BMPs) -2, -4, and -7. Gremlin appears to activate the extracellular regulated kinase (ERK) pathway in endothelial and tumor cells, and as a consequence to have direct cellular effects. To determine whether gremlin has direct effects in osteoblasts, independent of its BMP binding activity, we examined its effects in ST-2 murine stromal cell lines and in primary cultures of murine calvarial osteoblasts. Gremlin did not activate Signaling mothers against decapentaplegic (Smad), and suppressed the BMP-2 induced Smad 1/5/8 phosphorylation and the transactivation of the BMP/Smad reporter construct 12xSBE-Oc-pGL3, confirming its BMPs antagonizing activity. Neither gremlin nor BMP-2 induced ERK 1/2 activation in ST-2 cells or calvarial osteoblasts. Moreover, slight changes in culture conditions induced the phosphorylation of ERK independent from BMP or gremlin exposure. In conclusion, gremlin inhibits BMP-2 signaling and activity, and does not have independent actions on ERK signaling in osteoblasts. Consequently, gremlin activity in osteoblasts can be attributed only to its BMP antagonizing effects.
authors.affiliation: Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105-1299, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Zanotti
authors.forename: Anna
authors.initials: A
authors.lastname: Smerdel-Ramoya
authors.forename: Lisa
authors.initials: L
authors.lastname: Stadmeyer
authors.forename: Ernesto
authors.initials: E
authors.lastname: Canalis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D010006:Osteoblasts / Q000378:metabolism*; D010766:Phosphorylation; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D036341:Intercellular Signaling Peptides and Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C525719:Bmp2 protein, mouse; C113178:Grem1 protein, mouse