title: Estrogen preserves Fas ligand levels by inhibiting microRNA-181a in bone marrow-derived mesenchymal stem cells to maintain bone remodeling balance.
abstract: Estrogen protects bone loss by promoting Fas ligand (FasL) transcription in osteoclasts and osteoblasts to induce apoptosis of osteoclasts. Bone marrow-derived mesenchymal stem cells (BMMSCs) express FasL protein, which is necessary for BMMSCs to induce T-cell apoptosis in cell therapy. However, the physiologic function of FasL in BMMSCs is unknown. In this study, using an in vitro coculture system and an in vivo BMMSC transplantation assay, we found that BMMSCs potently induced apoptosis of osteoclasts through the FasL/Fas pathway. Estrogen was necessary for this process as a promoter of FasL protein accumulation in BMMSCs. Furthermore, estrogen elevated FasL protein accumulation, not by increasing FasL gene transcription, but through microRNA-mediated posttranscriptional regulation. In brief, estrogen down-regulated expression of miR-181a, a negative modulator of FasL targeting the 3'-UTR of FasL mRNA. Estrogen deficiency resulted in excessive miR-181a, which decreased FasL protein levels to suppress BMMSC-induced osteoclast apoptosis. Furthermore, knockdown of miR-181a recovered the BMMSC defect to induce osteoclast apoptosis during estrogen deficiency. Taken together, our results showed that estrogen preserves FasL protein accumulation by inhibiting miR-181a expression in BMMSCs to maintain bone remodeling balance, suggesting a novel mechanism by which estrogen preserves bone mass.
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.
authors.forename: Bingyi
authors.initials: B
authors.lastname: Shao
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liao
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shuai
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Su
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Jing
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China yanjin@fmmu.edu.cn yangdeqin@gmail.com.
authors.forename: Deqin
authors.initials: D
authors.lastname: Yang
authors.affiliation: *State Key Laboratory of Military Stomatology, Center for Tissue Engineering and State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, and Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China; The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing, China; Chongqing Research Center for Oral Diseases and Biomedical Science, Chongqing, China; and Institute of Neurobiology, Environment, and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China yanjin@fmmu.edu.cn yangdeqin@gmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016723:Bone Remodeling / Q000187:drug effects*; D004967:Estrogens / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; D004967:Estrogens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D035683:MicroRNAs; C529100:mirn181 microRNA, mouse
keywords: apoptosis; cell transplantation; gene regulation; osteoclast; osteoporosis