Alcohol Induces Cellular Senescence and Impairs Osteogenic Potential in Bone Marrow-Derived Mesenchymal Stem Cells.
OBJECTIVE
Chronic and excessive alcohol consumption is a high-risk factor for osteoporosis. Bone marrow-derived mesenchymal stem cells (BM-MSCs) play an important role in bone formation; however, they are vulnerable to ethanol (EtOH). The purpose of this research was to investigate whether EtOH could induce premature senescence in BM-MSCs and subsequently impair their osteogenic potential.


METHODS
Human BM-MSCs were exposed to EtOH ranging from 10 to 250 mM. Senescence-associated β-galactosidase (SA-β-gal) activity, cell cycle distribution, cell proliferation and reactive oxygen species (ROS) were evaluated. Mineralization and osteoblast-specific gene expression were evaluated during osteogenesis in EtOH-treated BM-MSCs. To investigate the role of silent information regulator Type 1 (SIRT1) in EtOH-induced senescence, resveratrol (ResV) was used to activate SIRT1 in EtOH-treated BM-MSCs.


RESULTS
EtOH treatments resulted in senescence-associated phenotypes in BM-MSCs, such as decreased cell proliferation, increased SA-β-gal activity and G0/G1 cell cycle arrest. EtOH also increased the intracellular ROS and the expression of senescence-related genes, such as p16INK4α and p21. The down-regulated levels of SIRT1 accompanied with suppressed osteogenic differentiation were confirmed in EtOH-treated BM-MSCs. Activation of SIRT1 by ResV partially counteracted the effects of EtOH by decreasing senescence markers and rescuing the inhibited osteogenesis.


CONCLUSIONS
EtOH treatments induced premature senescence in BM-MSCs in a dose-dependent manner that was responsible for EtOH-impaired osteogenic differentiation. Activation of SIRT1 was effective in ameliorating EtOH-induced senescence phenotypes in BMSCs and could potentially lead to a new strategy for clinically preventing or treating alcohol-induced osteoporosis.


OBJECTIVE
Ethanol (EtOH) treatments induce premature senescence in marrow-derived mesenchymal stem cells in a dose-dependent manner that is responsible for EtOH-impaired osteogenic differentiation. Activation of SIRT1 is effective in ameliorating EtOH-induced senescence phenotypes, which potentially leads to a new strategy for clinically treating alcohol-induced osteoporosis.
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215153, Jiangsu, China.|Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou 215007, China.|School of Biology and Basic Medical Sciences, Medical College, Soochow University, No. 199 Renai Road, Suzhou 215123, China.
Xi
X
Chen
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215153, Jiangsu, China.|Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou 215007, China.
Mao
M
Li
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215153, Jiangsu, China.|Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou 215007, China.
Jinku
J
Yan
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215153, Jiangsu, China.
Tao
T
Liu
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215153, Jiangsu, China.|Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou 215007, China.
Guoqing
G
Pan
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215153, Jiangsu, China.|Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou 215007, China.
Huilin
H
Yang
Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics and Division of Exercise Physiology, West Virginia University, PO Box 9196, One Medical Center Drive, Morgantown, WV 26505-9196, USA.
Ming
M
Pei
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215153, Jiangsu, China.|Orthopaedic Institute, Medical College, Soochow University, No. 708 Renmin Road, Suzhou 215007, China.
Fan
F
He
D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology
D000431:Ethanol