Download effect of polyamines on the osteogenic differentiation of human bone

11th ISSCR Annual Meeting, Boston, MA, USA, June 12-15, 2013.
SUPPRESSION OF POLYAMINE BIOSYNTHESIS PROMOTE
OSTEOGENIC DIFFERENTIATION OF HUMAN BONE
MARROW-DERIVED MESENCHYMAL STEM CELLS
Lee, Mon-Juan, Tsai, You-Shiang, Lin, Kuan-Liang
Department of BioScience Technology, Chang Jung Christian University, Tainan,
Taiwan
Polyamines are naturally occurring organic polycations that are ubiquitous in all
organisms, and are essential for cell proliferation and differentiation. Although
polyamines are involved in various cellular processes, their roles in stem cell
differentiation are relatively unexplored. Results from our previous studies suggest
that exogenous polyamines, including putrescine, spermidine, and spermine, were
capable of promoting osteogenic differentiation of human bone marrow-derived
mesenchymal stem cells (hBMSCs). To investigate the mechanism underlying the
osteogenic potential of polyamines and the crosstalk between pathways of
osteogenesis and polyamine metabolism, we treated hBMSCs with
-difluoromethylornithine (DFMO), the irreversible inhibitor of the polyamine
biosynthetic enzyme, ornithine decarboxylase (ODC), to determine whether
suppression of intracellular polyamine level affects the differentiation fate of
hBMSCs. Our results indicate that DFMO up-regulated alkaline phosphatase (ALP)
activity, and enhanced the mRNA expression of osteogenic genes such as
Runt-related transcription factor 2 (Runx2), ALP, osteocalcin and osteopontin. In
addition, extracellular matrix mineralization, a marker for osteoblast maturation, was
accelerated in the presence of DFMO. We then suppressed the gene expression of
ODC in hBMSCs using small interfering RNAs (siRNAs) designed against ODC
(siODC), and found that the mRNA level of osteogenic genes such as osteocalcin and
osteopontin were increased. These results suggest that suppression of polyamine
biosynthesis may be correlated with the induction of osteogenic differentiation, and
the level of intracellular polyamines may be manipulated to promote osteogenic
differentiation. Currently, the only drug approved by the U.S. Food and Drug
Administration (FDA) to stimulate bone formation is parathyroid hormone (PTH),
which possesses the risk of inducing osteosarcoma. Studies on DFMO, a
chemopreventive agent for cancer that is being evaluated in clinical trials, as novel
osteogenic inducer not only help to elucidate the role of polyamine metabolism in the
lineage commitment of stem cells, but also promote the development of
polyamine-derived new drugs that stimulate bone formation.
Keywords:
polyamines,
-difluoromethylornithine
(DFMO),
osteogenic
differentiation, small interfering RNA (siRNA), mesenchymal stem cells
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