Expression levels of insulin receptor substrate-1 modulate the osteoblastic differentiation of mesenchymal stem cells and osteosarcoma cells

Clara Contaldo, Timothy J. Myers, Cinzia Zucchini, Maria Cristina Manara, Claudia Chiodoni, Mario P. Colombo, Giordano Nicoletti, Pier Luigi Lollini, Tieshi Li, Lara Longobardi, Katia Scotlandi, Anna Spagnoli

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The insulin-like growth factor-1 system, including its critical mediator insulin receptor substrate-1 (IRS-1), is involved in regulating osteosarcoma (OS) cell proliferation or differentiation. The aim of this study is to define the role of IRS-1 in OS cells by assessing the contribution of IRS-1 in the differentiation of human and murine OS cell lines and mouse mesenchymal stem cells (MSCs) and found that the basal level of IRS-1 is important for the initiation of differentiation. Both down-regulation and over-expression of IRS-1 inhibited osteoblastic differentiation. In vivo studies showed that OS cells over-expressing IRS-1 have increased metastatic potential and tumor growth. The proteasome inhibitor MG-132 led to an increase in IRS-1 protein level that inhibited osteoblastic differentiation, suggesting a role for proteasomal regulation in maintaining the appropriate expression level of IRS-1. Thus, precise regulation of IRS-1 expression level is critical for determining the differentiating capacity of MSCs and OS cells, and that derangement of IRS-1 levels can be a critical step in OS transformation.

Original languageEnglish (US)
Pages (from-to)41-52
Number of pages12
JournalGrowth Factors
Volume32
Issue number1
DOIs
StatePublished - Feb 2014

    Fingerprint

Keywords

  • Insulin receptor substrate-1
  • Mesenchymal stem cells
  • Osteoblastic differentiation
  • Osteosarcoma

ASJC Scopus subject areas

  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Contaldo, C., Myers, T. J., Zucchini, C., Manara, M. C., Chiodoni, C., Colombo, M. P., Nicoletti, G., Lollini, P. L., Li, T., Longobardi, L., Scotlandi, K., & Spagnoli, A. (2014). Expression levels of insulin receptor substrate-1 modulate the osteoblastic differentiation of mesenchymal stem cells and osteosarcoma cells. Growth Factors, 32(1), 41-52. https://doi.org/10.3109/08977194.2013.870168