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Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation

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Abstract

Human bone marrow mesenchymal stem cells (MSCs) are pleiotrophic cells that differentiate to either adipocytes or osteoblasts as a result of crosstalk by specific signaling pathways including heme oxygenase (HO)-1/-2 expression. We examined the effect of inducers of HO-1 expression and inhibitors of HO activity on MSC differentiation to the osteoblast and following high glucose exposure. MSC cultured in osteogenic medium increased expression of osteonectin, Runt-related transcription factor 2 (RUNX-2), osteocalcin, and alkaline phosphatase. HO-1 expression during differentiation was initially decreased and then followed by a rebound increase after 15 days of culture. Additionally, the effect of HO-1 on osteoblasts appears different to that seen in adipocyte stem cells. On addition of a cobalt compound, the resultant induction of HO-1 decreases adipogenesis. Moreover, glucose (30 mM) inhibited osteoblast differentiation, as evidenced by decreased bone morphogenetic protein (BMP)-2, osteonectin, osteocalcin, and osteoprotegerin (OPG). In contrast, MSC-derived adipocytes were increased by glucose. Increased HO-1 expression increased the levels of osteonectin, OPG, and BMP-2. Inhibition of HO activity prevented the increase in osteonectin and potentiated the decrease of osteocalcin and OPG in cells exposed to high glucose levels. Furthermore, targeting HO-1 expression increased pAMPK and endothelial nitric oxide synthase (eNOS) and restored osteoblastic markers. Our findings suggest that targeting HO-1 gene expression attenuates the hyperglycemia-mediated decrease in MSC-derived osteoblast differentiation. Finally, the mechanism underlying the HO-1-specific cell effect on osteoblasts and adipocytes is yet to be explored. Thus, the targeting of HO-1 gene expression presents a portal to increase osteoblast function and differentiation and attenuate osteoporosis by promoting bone formation.

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Acknowledgments

This work was supported by NIH grants DK068134, HL55601, and HL34300 (to N.G.A.).

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Authors and Affiliations

  1. Department of Biological Chemistry, Medical Chemistry and Molecular Biology, University of Catania, Catania, Italy

    Ignazio Barbagallo & Angelo Vanella

  2. Department of Biomedical Sciences, Section of Hematology, University of Catania, Catania, Italy

    Daniele Tibullo, Cesarina Giallongo, Nunziatina Parrinello, Giuseppe A. Palumbo & Francesco Di Raimondo

  3. Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Education Bldg., 3000 Arlington Avenue, Toledo, OH, 43614-2598, USA

    Dong Hyun Kim, Luca Vanella & Nader G. Abraham

  4. Department of Medicine, New York Medical College, Valhalla, NY, USA

    Stephen J. Peterson & Nader G. Abraham

  5. Department of Orthopedics, New York Medical College, Valhalla, NY, USA

    David Asprinio

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  1. Ignazio Barbagallo
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  2. Angelo Vanella
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  3. Stephen J. Peterson
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  4. Dong Hyun Kim
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  5. Daniele Tibullo
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  6. Cesarina Giallongo
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  7. Luca Vanella
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  8. Nunziatina Parrinello
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  9. Giuseppe A. Palumbo
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  10. Francesco Di Raimondo
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  11. Nader G. Abraham
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  12. David Asprinio
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Correspondence to Nader G. Abraham.

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Barbagallo, I., Vanella, A., Peterson, S.J. et al. Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation. J Bone Miner Metab 28, 276–288 (2010). https://doi.org/10.1007/s00774-009-0134-y

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