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NVP‐BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells
Author(s) -
Martin Sally K,
Fitter Stephen,
Bong Li Fei,
Drew Jennifer J,
Gronthos Stan,
Shepherd Peter R,
Zannettino Andrew CW
Publication year - 2010
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.114
Subject(s) - pi3k/akt/mtor pathway , mesenchymal stem cell , microbiology and biotechnology , cancer research , osteoblast , stromal cell , chemistry , biology , signal transduction , in vitro , biochemistry
Osteoblasts are bone‐forming cells derived from mesenchymal stromal cells (MSCs) that reside within the bone marrow. In response to a variety of factors, MSCs proliferate and differentiate into mature, functional osteoblasts. Several studies have shown previously that suppression of the PI3K and mTOR signaling pathways in these cells strongly promotes osteogenic differentiation, which suggests that inhibitors of these pathways may be useful as anabolic bone agents. In this study we examined the effect of BEZ235, a newly developed dual PI3K and mTOR inhibitor currently in phase I–II clinical trials for advanced solid tumors, on osteogenic differentiation and function using primary MSC cultures. Under osteoinductive conditions, BEZ235 strongly promotes osteogenic differentiation, as evidenced by an increase in mineralized matrix production, an upregulation of genes involved in osteogenesis, including bone morphogenetic proteins ( BMP2, ‐4, and ‐6 ) and transforming growth factor β1 (TGF‐β1) superfamily members ( TGFB1 , TGFB2 , and INHBE ), and increased activation of SMAD signaling molecules. In addition, BEZ235 enhances de novo bone formation in calvarial organotypic cultures. Using pharmacologic inhibitors to delineate mechanism, our studies reveal that suppression of mTOR and, to a much lesser extent PI3K p110α, mediates the osteogenic effects of BEZ235. As confirmation, shRNA‐mediated knockdown of mTOR enhances osteogenic differentiation and function in SAOS‐2 osteoblast‐like cells. Taken together, our findings suggest that BEZ235 may be useful in treating PI3K/mTOR‐dependent tumors associated with bone loss, such as the hematologic malignancy multiple myeloma. © 2010 American Society for Bone and Mineral Research.