HO-1 expression increases mesenchymal stem cell-derived osteoblasts but decreases adipocyte lineage.
Human bone marrow mesenchymal stem cells (MSC) are pleiotropic cells that differentiate to either adipocytes or osteoblasts as a result of cross-talk 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 adipocyte lineage. HO-1 expression is increased during osteoblast stem cell development but remains elevated at 25 days. The increase in HO-1 levels precedes an increase in alkaline phosphatase (AP) activity and an increase in BMP, osteonectin and RUNX-2 mRNA. Induction of HO-1 by osteogenic growth peptide (OGP) was associated with an increase in BMP-2 and osteonectin. Exposure of MSC to high glucose levels decreased osteocalcin and osteogenic protein expression, which was reversed by upregulation of the OGP-mediated increase in HO-1 expression. The glucose-mediated decrease in HO-1 resulted in decreased levels of pAMPK, pAKT and the eNOS signaling pathway and was reversed by OGP. In contrast, MSC-derived adipocytes were increased by glucose. HO-1 siRNA decreased HO-1 expression but increased adipocyte stem cell differentiation and the adipogenesis marker, PPARgamma. Thus, upregulation of HO-1 expression shifts the balance of MSC differentiation in favor of the osteoblast lineage. In contrast, a decrease in HO-1 or exposure to glucose drives the MSC towards adipogenesis. Thus, targeting HO-1 expression is a portal to increased osteoblast stem cell differentiation and to the attenuation of osteoporosis by the promotion of bone formation.
Vanella
Luca
L
Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH, USA.
Kim
Dong Hyun
DH
Asprinio
David
D
Peterson
Stephen J
SJ
Barbagallo
Ignazio
I
Vanella
Angelo
A
Goldstein
Dove
D
Ikehara
Susumu
S
Kappas
Attallah
A
Abraham
Nader G
NG
D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology
D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D047495:PPAR gamma; D034741:RNA, Small Interfering; D015675:Osteocalcin; C074533:osteogenic growth peptide; D051547:Heme Oxygenase-1; D005947:Glucose