Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells.

Full Abstract

Epidermal growth factor receptor (EGFR)-mediated signaling helps regulate bone development and healing through its effects on osteogenic cells. Here, we show how EGFR activity and osteogenic differentiation responses in primary human bone marrow-derived multipotent stromal cells (MSCs) are influenced by presenting covalently tethered epidermal growth factor (tEGF) on the culture substratum, a presentation mode that reduces EGFR internalization and restricts signaling to the cell surface. In both absence and presence of tEGF, MSCs increase expression levels of EGFR and its heterodimerization partner HER2 during the course of osteogenic differentiation. tEGF substrata increased levels of phosphorylated EGFR and phosphorylated extracellular regulated kinase (ERK) compared to control substrata, and these elevations were associated with a twofold enhancement of MSC alkaline phosphatase activity at day 7 and matrix mineralization at day 21. Surprisingly, addition of soluble EGF (sEGF) to cells cultured on tEGF substrata reduces osteogenic differentiation, even though EGFR signaling is more strongly activated in acute, short-term manner by sEGF treatment than by tEGF treatment. A striking concomitant result of the sEGF effects is near-complete downregulation of EGFR and HER2, demonstrating that the tEGF/EGFR interaction is dynamically reversible even though temporally sustained. Taken together, our results show that enhanced MSC osteogenic differentiation corresponds to a sustained combination of receptor expression and ligand presentation, both of which are maintained by tEGF.

Author information

Author/s: Platt, Manu O (MO); Roman, Arian J (AJ); Wells, Alan (A); Lauffenburger, Douglas A (DA); Griffith, Linda G (LG);

Affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Grants: P40RR017447 (Agency:NCRR NIH HHS) ; R01-DE 019523-10 (Agency:NIDCR NIH HHS) ; R01-GM059870-07 (Agency:NIGMS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of cellular physiology (J Cell Physiol), published in United States. (Language: eng)

Reference: 2009-Nov; vol 221 (issue 2) : pp 306-17

Dates: Created 2009/08/27; Completed 2009/09/09;

PMID: 19544388, status: MEDLINE (last retrieval date: 9/9/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Bone Marrow Cells - cytology; enzymology
Bone Matrix - metabolism
Calcification, Physiologic
Cell Differentiation
Cell Line, Transformed
Cell Proliferation
Enzyme Activation
Epidermal Growth Factor - genetics; metabolism
Humans
Ligands
Models, Biological

Models, Biological
Multipotent Stem Cells - cytology; enzymology
Osteogenesis
Phosphorylation
RNA, Messenger - genetics; metabolism
Receptor, Epidermal Growth Factor - metabolism
Signal Transduction
Solubility
Stromal Cells - cytology; enzymology
Time Factors
Transforming Growth Factor alpha - genetics; metabolism

Associated Chemicals: Ligands (0) ; RNA, Messenger (0) ; Transforming Growth Factor alpha (0) ; Epidermal Growth Factor (62229-50-9) ; Receptor, Epidermal Growth Factor (EC 2.7.1.112)

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