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Oxysterol‐induced osteogenic differentiation of marrow stromal cells is regulated by Dkk‐1 inhibitable and PI3‐kinase mediated signaling
Author(s) -
Amantea Christopher M.,
Kim WooKyun,
Meliton Vicente,
Tetradis Sotirios,
Parhami Farhad
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21840
Subject(s) - wnt signaling pathway , oxysterol , microbiology and biotechnology , hedgehog signaling pathway , chemistry , wnt3a , frizzled , stromal cell , dishevelled , signal transduction , cyclopamine , lrp5 , cancer research , biology , biochemistry , cholesterol
Osteoporosis and its complications cause morbidity and mortality in the aging population, and result from increased bone resorption by osteoclasts in parallel with decreased bone formation by osteoblasts. A widely accepted strategy for improving bone health is targeting osteoprogenitor cells in order to stimulate their osteogenic differentiation and bone forming properties through the use of osteoinductive/anabolic factors. We previously reported that specific naturally occurring oxysterols have potent osteoinductive properties, mediated in part through activation of hedgehog signaling in osteoprogenitor cells. In the present report, we further demonstrate the molecular mechanism(s) by which oxysterols induce osteogenesis. In addition to activating the hedgehog signaling pathway, oxysterol‐induced osteogenic differentiation is mediated through a Wnt signaling‐related, Dkk‐1‐inhibitable mechanism. Bone marrow stromal cells (MSC) treated with oxysterols demonstrated increased expression of osteogenic differentiation markers, along with selective induced expression of Wnt target genes. These oxysterol effects, which occurred in the absence of β‐catenin accumulation or TCF/Lef activation, were inhibited by the hedgehog pathway inhibitor, cyclopamine, and/or by the Wnt pathway inhibitor, Dkk‐1. Furthermore, the inhibitors of PI3‐Kinase signaling, LY 294002 and wortmanin, inhibited oxysterol‐induced osteogenic differentiation and induction of Wnt signaling target genes. Finally, activators of canonical Wnt signaling, Wnt3a and Wnt1, inhibited spontaneous, oxysterol‐, and Shh‐induced osteogenic differentiation of bone marrow stromal cells, suggesting the involvement of a non‐canonical Wnt pathway in pro‐osteogenic differentiation events. Osteogenic oxysterols are, therefore, important small molecule modulators of critical signaling pathways in pluripotent mesenchymal cells that regulate numerous developmental and post‐developmental processes. J. Cell. Biochem. 105: 424–436, 2008. © 2008 Wiley‐Liss, Inc.