title: Gene disruption of Spred-2 causes dwarfism.
abstract: The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase (MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2(-/-) mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2(-/-) chondrocytes in comparison to Spred-2(+/+) chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.
authors.affiliation: Institut für Klinische Biochemie und Pathobiochemie, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Bundschu
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.forename: Melanie
authors.initials: M
authors.lastname: Ullrich
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Engelhardt
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Kai
authors.initials: K
authors.lastname: Schuh
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012097:Repressor Proteins; C500760:SPRED2 protein, human