Chemistry and Physics Faculty Articles

Title

Human bone marrow-derived stem cell proliferation is inhibited by hepatocyte growth factor via increasing the cell cycle inhibitors p53, p21 and p27

Document Type

Article

Publication Date

12-2011

Publication Title

Bone

Keywords

Hepatocyte growth factor, Stem cell, Mesenchymal stem cell, 1, 25-dihydroxyvitamin D, Osteoprogenitors

ISSN

8756-3282

Volume

49

Issue/No.

6

First Page

1194

Last Page

1204

Abstract

Human bone marrow-derived stem cells (hMSCs) are a major source of osteoprogenitors. Hepatocyte growth factor (HGF), a glycoprotein constitutively produced by hMSCs, is reported to act on differentiated osteoblasts and also osteoclasts. Moreover, HGF has been shown by us and others to enhance osteoblastic differentiation from hMSCs. Typically, the pro-differentiation effects of HGF have required cooperative action with regulatory factors such as vitamin D or bone matrix material. Here, we have pursued the molecular mechanisms underlying the osteogenic effect of HGF on hMSCs, the principal precursors to bone forming cells. HGF treatment of hMSCs reduced the cell number over time and increased G1/S cell-cycle arrest compared to control (non-treated) cells. RT-qPCR showed treatment with HGF increased gene expression of the cell-cycle inhibitors p53, p21, and p27, possibly explaining the cell growth inhibition and G1 arrest, a step critical to phenotypic differentiation. Transfection of siRNA specific for cMet, the HGF receptor, eliminated the HGF anti-proliferation effect on hMSCs and the HGF-mediated increase in p53, p21, and p27, strongly supporting a role for these cell-cycle inhibitors in HGF's regulation of hMSCs. HGF in combination with a known inducer of osteogenic differentiation, 1,25-dihydroxyvitamin D, significantly increased cell maturation/differentiation as indicated by an increase in several osteoblast markers. Taken together these results demonstrate that HGF significantly enhances hMSC osteoblast differentiation by 1,25-dihydroxyvitamin D.

Comments

This work was supported by Merit Review awards from the Department of Veterans Affairs to CP-S, PCS, BAR, and GAH. We would like to thank Dr. Paul Reuben for suggestions and critical discussions regarding this work. We thank David Vazquez and B. Nubia Rodriguez for excellent technical assistance. Dr. Howard is the recipient of a Senior Research Career Scientist award from the Department of Veterans Affairs.

DOI

10.1016/j.bone.2011.08.023

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