title: Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy.
abstract: The molecular basis underlying the clinical phenotype in bone diseases is customarily associated with abnormal extracellular matrix structure and/or properties. More recently, cellular malfunction has been identified as a concomitant causative factor and increased attention has focused on stem cells differentiation. Classic osteogenesis imperfecta (OI) is a prototype for heritable bone dysplasias: it has dominant genetic transmission and is caused by mutations in the genes coding for collagen I, the most abundant protein in bone. Using the Brtl mouse, a well-characterized knockin model for moderately severe dominant OI, we demonstrated an impairment in the differentiation of bone marrow progenitor cells toward osteoblasts. In mutant mesenchymal stem cells (MSCs), the expression of early (Runx2 and Sp7) and late (Col1a1 and Ibsp) osteoblastic markers was significantly reduced with respect to wild type (WT). Conversely, mutant MSCs generated more colony-forming unit-adipocytes compared to WT, with more adipocytes per colony, and increased number and size of triglyceride drops per cell. Autophagy upregulation was also demonstrated in mutant adult MSCs differentiating toward osteogenic lineage as consequence of endoplasmic reticulum stress due to mutant collagen retention. Treatment of the Brtl mice with the proteasome inhibitor Bortezomib ameliorated both osteoblast differentiation in vitro and bone properties in vivo as demonstrated by colony-forming unit-osteoblasts assay and peripheral quantitative computed tomography analysis on long bones, respectively. This is the first report of impaired MSC differentiation to osteoblasts in OI, and it identifies a new potential target for the pharmacological treatment of the disorder.
authors.affiliation: Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Via Taramelli 3/B, Pavia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gioia
authors.forename: Cristina
authors.initials: C
authors.lastname: Panaroni
authors.forename: Roberta
authors.initials: R
authors.lastname: Besio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palladini
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giansanti
authors.forename: Ivana A
authors.initials: IA
authors.lastname: Scovassi
authors.forename: Simona
authors.initials: S
authors.lastname: Villani
authors.forename: Isabella
authors.initials: I
authors.lastname: Villa
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Ruggero
authors.initials: R
authors.lastname: Tenni
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010013:Osteogenesis Imperfecta / Q000378:metabolism* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib