title: p38α MAPK Regulates Lineage Commitment and OPG Synthesis of Bone Marrow Stromal Cells to Prevent Bone Loss under Physiological and Pathological Conditions.
abstract: Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of differentiating into osteoblasts, chondrocytes, and adipocytes. Skewed differentiation of BM-MSCs contributes to the pathogenesis of osteoporosis. Yet how BM-MSC lineage commitment is regulated remains unclear. We show that ablation of p38α in Prx1+ BM-MSCs produced osteoporotic phenotypes, growth plate defects, and increased bone marrow fat, secondary to biased BM-MSC differentiation from osteoblast/chondrocyte to adipocyte and increased osteoclastogenesis and bone resorption. p38α regulates BM-MSC osteogenic commitment through TAK1-NF-κB signaling and osteoclastogenesis through osteoprotegerin (OPG) production by BM-MSCs. Estrogen activates p38α to maintain OPG expression in BM-MSCs to preserve the bone. Ablation of p38α in BM-MSCs positive for Dermo1, a later BM-MSC marker, only affected osteogenic differentiation. Thus, p38α mitogen-activated protein kinase (MAPK) in Prx1+ BM-MSCs acts to preserve the bone by promoting osteogenic lineage commitment and sustaining OPG production. This study thus unravels previously unidentified roles for p38α MAPK in skeletal development and bone remodeling.
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cong
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jia
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Soma
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Shoutao
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xizhi
authors.initials: X
authors.lastname: Guo
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Ma
authors.affiliation: The Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
authors.forename: Jenny Fang
authors.initials: JF
authors.lastname: Ling Chau
authors.affiliation: Division of Molecular Medicine, Departments of Anesthesiology, Medicine and Physiology, Molecular Biology Institute, Cardiovascular Research Laboratories, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University affiliated the Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Zhang
authors.affiliation: Department of Prosthodontics, Oral Bioengineering and Regenerative Medicine Lab, Shanghai Research Institute of Stomatology, Ninth People's Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, China.
authors.forename: Xinquan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: liuhj@sjtu.edu.cn.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: libj@sjtu.edu.cn.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004967:Estrogens / Q000172:deficiency / Q000494:pharmacology; D006132:Growth Plate / Q000002:abnormalities / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism; D053244:Osteoprotegerin / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D004967:Estrogens; D018398:Homeodomain Proteins; D020930:MAP Kinase Kinase Kinases; D048308:Mitogen-Activated Protein Kinase 14; D016328:NF-kappa B; D053244:Osteoprotegerin; D000099151:MAP Kinase Kinase Kinase 7; C489936:Prrx1 protein, mouse