Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation.
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.
Barbagallo
Ignazio
I
Department of Biological Chemistry, Medical Chemistry and Molecular Biology, University of Catania, Catania, Italy.
Vanella
Angelo
A
Peterson
Stephen J
SJ
Kim
Dong Hyun
DH
Tibullo
Daniele
D
Giallongo
Cesarina
C
Vanella
Luca
L
Parrinello
Nunziatina
N
Palumbo
Giuseppe A
GA
Di Raimondo
Francesco
F
Abraham
Nader G
NG
Asprinio
David
D
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000201:enzymology*; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D015415:Biomarkers; D004791:Enzyme Inhibitors; D053244:Osteoprotegerin; D012333:RNA, Messenger; C506030:TNFRSF11B protein, human; D015675:Osteocalcin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D055372:AMP-Activated Protein Kinases