title: Differential expression of both extracellular and intracellular proteins is involved in the lethal or nonlethal phenotypic variation of BrtlIV, a murine model for osteogenesis imperfecta.
abstract: This study used proteomic and transcriptomic techniques to understand the molecular basis of the phenotypic variability in the bone disorder osteogenesis imperfecta (OI). Calvarial bone mRNA expression was evaluated by microarray, real-time, and comparative RT-PCR and the bone proteome profile was analyzed by 2-DE, MS, and immunoblotting in the OI murine model BrtlIV, which has either a moderate or a lethal OI outcome. Differential expression analysis showed significant changes for eight proteins. The expression of the ER stress-related protein Gadd153 was increased in lethal mice, whereas expression of the chaperone alphaB crystallin was increased in nonlethal mice, suggesting that the intracellular machinery is involved in the modulation of the OI phenotype. Furthermore, in lethal BrtlIV, the increased expression of the cartilaginous proteins Prelp, Bmp6, and Bmp7 and the lower expression of the bone matrix proteins matrilin 4, microfibril-associated glycoprotein 2, and thrombospondin 3 revealed that both a delay in skeletal development and an alteration in extracellular matrix composition influence OI outcomes. Differentially expressed proteins identified in this model offer a starting point for elucidating the molecular basis of phenotypic variability, a characteristic common to many genetic disorders. The first reference 2-DE map for murine calvarial tissue is also reported.
authors.affiliation: Department of Biochemistry "A. Castellani", Section of Medicine and Pharmacy, University of Pavia, Pavia, Italy. aforlino@unipv.it
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Chiara
authors.initials: C
authors.lastname: Tani
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.forename: Anna
authors.initials: A
authors.lastname: Lupi
authors.forename: Elena
authors.initials: E
authors.lastname: Campari
authors.forename: Benedetta
authors.initials: B
authors.lastname: Gualeni
authors.forename: Laura
authors.initials: L
authors.lastname: Bianchi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Armini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cetta
authors.forename: Luca
authors.initials: L
authors.lastname: Bini
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D001842:Bone and Bones / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005804:Genes, Lethal; D005819:Genetic Markers; D014644:Genetic Variation; D051379:Mice; D046228:Microarray Analysis; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; C497250:Ddit3 protein, mouse; D005819:Genetic Markers; D051742:Transcription Factor CHOP