title: p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner.
abstract: Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α-/-cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.
authors.affiliation: Dept. of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.|Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cong
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.|Department of Biochemistry and Molecular cellular Biology Shanghai Jiaotong University, School of Medicine, 280 Chongqing Rd, Shanghai, 200025, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jia
authors.affiliation: Dept. of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.|Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Dept. of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.|Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Shoutao
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: James
authors.initials: J
authors.lastname: Yeh
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, CA90095, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Ao
authors.affiliation: Dept. of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.|Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
authors.affiliation: Dept. of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.|Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D016723:Bone Remodeling; D001862:Bone Resorption / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology*; D010012:Osteogenesis; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D055114:X-Ray Microtomography
chemical_list: D055396:Bone Morphogenetic Protein 2; D017362:Cyclic AMP Response Element-Binding Protein; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D048308:Mitogen-Activated Protein Kinase 14; C045073:Cre recombinase; D019426:Integrases