Betacellulin inhibits osteogenic differentiation and stimulates proliferation through HIF-1α
Open Access
- 18 February 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell and tissue research
- Vol. 340 (1), 81-89
- https://doi.org/10.1007/s00441-010-0929-0
Abstract
Cellular signaling via epidermal growth factor (EGF) and EGF-like ligands can determine cell fate and behavior. Osteoblasts, which are responsible for forming and mineralizing osteoid, express EGF receptors and alter rates of proliferation and differentiation in response to EGF receptor activation. Transgenic mice over-expressing the EGF-like ligand betacellulin (BTC) exhibit increased cortical bone deposition; however, because the transgene is ubiquitously expressed in these mice, the identity of cells affected by BTC and responsible for increased cortical bone thickness remains unknown. We have therefore examined the influence of BTC upon mesenchymal stem cell (MSC) and pre-osteoblast differentiation and proliferation. BTC decreases the expression of osteogenic markers in both MSCs and pre-osteoblasts; interestingly, increases in proliferation require hypoxia-inducible factor-alpha (HIF-α), as an HIF antagonist prevents BTC-driven proliferation. Both MSCs and pre-osteoblasts express EGF receptors ErbB1, ErbB2, and ErbB3, with no change in expression under osteogenic differentiation. These are the first data that demonstrate an influence of BTC upon MSCs and the first to implicate HIF-α in BTC-mediated proliferation.Keywords
This publication has 44 references indexed in Scilit:
- Concomitant inhibition of prolyl hydroxylases and ROCK initiates differentiation of mesenchymal stem cells and PC12 towards the neuronal lineageBiochemical and Biophysical Research Communications, 2008
- The role of hypoxia-inducible factors in tumorigenesisCell Death & Differentiation, 2008
- Activation of the hypoxia-inducible factor-1α pathway accelerates bone regenerationProceedings of the National Academy of Sciences, 2008
- The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal developmentJCI Insight, 2007
- Hypoxia-Independent Overexpression of Hypoxia-Inducible Factor 1α as an Early Change in Mouse HepatocarcinogenesisCancer Research, 2006
- Cross-talk between Epidermal Growth Factor Receptor and Hypoxia-inducible Factor-1α Signal Pathways Increases Resistance to Apoptosis by Up-regulating Survivin Gene ExpressionJournal of Biological Chemistry, 2006
- EGF–ERBB signalling: towards the systems levelNature Reviews Molecular Cell Biology, 2006
- Hypoxia and hypoxia-inducible factor-1α promote growth factor-induced proliferation of human vascular smooth muscle cellsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- The EGFR family and its ligands in human cancerEuropean Journal Of Cancer, 2001