Journal Article

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

Barbagallo, Ignazio, Vanella, Luca, Abraham, Nader G, Tibullo, Daniele, Raimondo, Francesco Di, Peterson, Stephen J, Giallongo, Cesarina, Vanella, Angelo, Parrinello, Nunziatina, Palumbo, Giuseppe A, Kim, Dong Hyun, Asprinio, David

2010

Overview

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.

• Publisher: Japan : Springer Japan,Springer Japan,Springer,Springer Nature B.V
• Subject: Adipogenesis / Adipogenesis - drug effects / AMP-Activated Protein Kinases / AMP-Activated Protein Kinases - metabolism / antagonists & inhibitors / Biological and medical sciences / Biomarkers / Biomarkers - metabolism / Bone Diseases, Metabolic / Bone Diseases, Metabolic - etiology / Bone Diseases, Metabolic - prevention & control / Bone marrow / Cell Differentiation / Cell Differentiation - drug effects / Cell differentiation, maturation, development, hematopoiesis / Cell physiology / Cells, Cultured / complications / cytology / Diabetes / Diabetes Mellitus, Type 2 / Diabetes Mellitus, Type 2 - complications / Diabetes. Impaired glucose tolerance / Diseases of the osteoarticular system / Dose-Response Relationship, Drug / drug effects / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Enzyme Inhibitors / Enzyme Inhibitors - pharmacology / enzymology / etiology / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Fundamental and applied biological sciences. Psychology / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Enzymologic - drug effects / genetics / Glucose / Heme Oxygenase-1 / Heme Oxygenase-1 - antagonists & inhibitors / Heme Oxygenase-1 - genetics / Heme Oxygenase-1 - metabolism / HO-1 / Humans / Hyperglycemia / Hyperglycemia - physiopathology / Medical sciences / Medicine / Medicine & Public Health / Mesenchymal Stem Cells / Mesenchymal Stem Cells - cytology / Mesenchymal Stem Cells - enzymology / Metabolic Diseases / metabolism / Molecular and cellular biology / MSC / Nitric oxide / Nitric Oxide Synthase Type III / Nitric Oxide Synthase Type III - metabolism / Original Article / Orthopedics / Osteoblasts / Osteoblasts - cytology / Osteoblasts - enzymology / Osteocalcin / Osteocalcin - genetics / Osteocalcin - metabolism / Osteogenesis / Osteogenesis - drug effects / Osteopenia / Osteoporosis / Osteoporosis - etiology / Osteoporosis - prevention & control / Osteoporosis. Osteomalacia. Paget disease / Osteoprotegerin / Osteoprotegerin - genetics / Osteoprotegerin - metabolism / pharmacology / physiopathology / prevention & control / RNA, Messenger / RNA, Messenger - metabolism / Stem cells / Time Factors