Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: A new target for osteogenesis imperfecta pharmacological therapy

Roberta Gioia, Cristina Panaroni, Roberta Besio, Giovanni Palladini, Giampaolo Merlini, Vincenzo Giansanti, Ivana A. Scovassi, Simona Villani, Isabella Villa, Anna Villa, Paolo Vezzoni, Ruggero Tenni, Antonio Rossi, Joan C. Marini, Antonella Forlino

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1465-1476
Number of pages12
JournalStem Cells
Issue number7
Publication statusPublished - Jul 2012


  • Adipogenesis
  • Adult stem cell
  • Adult stem cells differentiation
  • Autophagy
  • Osteoblastogenesis
  • Osteogenesis imperfecta

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine


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