Reduction in Gsα induces osteogenic differentiation in human mesenchymal stem cells

Steven A. Lietman, Changlin Ding, David W. Cooke, Michael A. Levine

Research output: Contribution to journalArticlepeer-review

Abstract

We hypothesized that a decrease in Gsα expression occurs with osteogenic differentiation and that when Gsα expression was decreased by antisense oligonucleotides or direct inhibition of protein kinase A there was a concomitant increase in Runx2/Cbfa1. We also investigated the mechanism involved in the change in Runx2/Cbfa1 levels and whether the expression of other genes known to be involved in bone formation was altered. There was a decrease in Gsα expression with osteogenic differentiation and antisense oligonucleotides, and protein kinase A inhibition led to increased expression and DNA binding of the osteoblast-specific Runx2/Cbfa1. Additionally, with decreased Gsα expression or protein kinase A inhibition, Runx2/Cbfa1 protein was serine phosphorylated and ubiquitinated less. Microarray analysis, after the addition of antisense Gsα, showed a more than 10-fold increase in collagen Type I Alpha 2 mRNA (a target of Runx2/Cbfa1). These data show that reduced expression of Gsα can induce an osteoblast-like phenotype. The results also indicate a potential pathophysiologic role in patients with heterozygous inactivating mutations in GNAS1, the gene for the alpha chain (Gsα) of the heterotrimeric G protein, present in three disorders with ectopic intramembranous bone: Albright's hereditary osteodystrophy, progressive osseous heteroplasia, and osteoma cutis.

Original languageEnglish (US)
Pages (from-to)231-238
Number of pages8
JournalClinical orthopaedics and related research
Issue number434
DOIs
StatePublished - May 2005

ASJC Scopus subject areas

  • Surgery
  • Orthopedics and Sports Medicine

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