title: Chronic High Dose Alcohol Induces Osteopenia via Activation of mTOR Signaling in Bone Marrow Mesenchymal Stem Cells.
abstract: Chronic consumption of excessive alcohol results in reduced bone mass, impaired bone structure, and increased risk of bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are not fully understood. Here, we show that high dose chronic alcohol consumption reduces osteogenic differentiation and enhances adipogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs), leading to osteopenia in a mouse model. Mechanistically, impaired osteo/adipogenic lineage differentiation of BMMSCs is due to activation of a phosphatidylinositide 3-kinase/AKT/mammalian target of rapamycin (mTOR) signaling cascade, resulting in downregulation of runt-related transcription factor 2 and upregulation of peroxisome proliferator-activated receptor gamma via activation of p70 ribosomal protein S6 kinase. Blockage of the mTOR pathway by rapamycin treatment ameliorates alcohol-induced osteopenia by rescuing impaired osteo/adipogenic lineage differentiation of BMMSCs. In this study, we identify a previously unknown mechanism by which alcohol impairs BMMSC lineage differentiation and reveal a potential rapamycin-based drug therapy for alcohol-induced osteoporosis. Stem Cells 2016;34:2157-2168.
authors.affiliation: Department of Pediatric Dentistry, School of Stomatology, China Medical University, Shenyang, China.|Liaoning Province Key Laboratory of Oral Disease, Shenyang, China.|Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.|Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Kou
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.|Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Chider
authors.initials: C
authors.lastname: Chen
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.|Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yu
authors.affiliation: Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Su
authors.affiliation: UCLA School of Dentistry, Los Angeles, California, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.|Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.affiliation: Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000209:etiology* / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D019070:Cell Lineage / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008819:Mice, Nude; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000431:Ethanol; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Adipogenesis; Alcohol consumption; Bone marrow mesenchymal stem cells; Osteogenesis; Osteoporosis; Rapamycin