Journal of Bone and Mineral Metabolism

, Volume 28, Issue 3, pp 276–288 | Cite as

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

  • Ignazio Barbagallo
  • Angelo Vanella
  • Stephen J. Peterson
  • Dong Hyun Kim
  • Daniele Tibullo
  • Cesarina Giallongo
  • Luca Vanella
  • Nunziatina Parrinello
  • Giuseppe A. Palumbo
  • Francesco Di Raimondo
  • Nader G. AbrahamEmail author
  • David Asprinio
Original Article


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.


Osteopenia Osteoporosis MSC Diabetes HO-1 



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


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Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2009

Authors and Affiliations

  • Ignazio Barbagallo
    • 1
  • Angelo Vanella
    • 1
  • Stephen J. Peterson
    • 4
  • Dong Hyun Kim
    • 3
  • Daniele Tibullo
    • 2
  • Cesarina Giallongo
    • 2
  • Luca Vanella
    • 3
  • Nunziatina Parrinello
    • 2
  • Giuseppe A. Palumbo
    • 2
  • Francesco Di Raimondo
    • 2
  • Nader G. Abraham
    • 3
    • 4
    Email author
  • David Asprinio
    • 5
  1. 1.Department of Biological Chemistry, Medical Chemistry and Molecular BiologyUniversity of CataniaCataniaItaly
  2. 2.Department of Biomedical Sciences, Section of HematologyUniversity of CataniaCataniaItaly
  3. 3.Department of Physiology and PharmacologyUniversity of Toledo College of MedicineToledoUSA
  4. 4.Department of MedicineNew York Medical CollegeValhallaUSA
  5. 5.Department of OrthopedicsNew York Medical CollegeValhallaUSA

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