title: Parathyroid Hormone-Related Protein Protects Osteoblastic Cells From Oxidative Stress by Activation of MKP1 Phosphatase.
abstract: Oxidative damage is an important contributor to the morphological and functional changes in osteoporotic bone. Aging increases the levels of reactive oxygen species (ROS) that cause oxidative stress and induce osteoblast apoptosis. ROS modify several signaling responses, including mitogen-activated protein kinase (MAPK) activation, related to cell survival. Both parathyroid hormone (PTH) and its bone counterpart, PTH-related protein (PTHrP), can regulate MAPK activation by modulating MAPK phosphatase-1 (MKP1). Thus, we hypothesized that PTHrP might protect osteoblasts from ROS-induced apoptosis by targeting MKP1. In osteoblastic MC3T3-E1 and MG-63 cells, H2O2triggered p38, JNK, ERK and p66Shcphosphorylation, and cell apoptosis. Meanwhile, PTHrP (1-37) rapidly but transiently increased ERK and Akt phosphorylation without affecting p38, JNK, or p66Shcactivation. H2O2-induced p38 and ERK phosphorylation and apoptosis were both decreased by pre-treatment with specific kinase inhibitors or PTHrP (1-37) in both osteoblastic cell types. These dephosphorylating and prosurvival actions of PTHrP (1-37) were prevented by a phosphatase inhibitor cocktail, the phosphatase MKP1 inhibitor sanguinarine or a MKP1 siRNA. PTHrP (1-37) promptly enhanced MKP1 protein and gene expression and MKP1-dependent catalase activity in osteoblastic cells. Furthermore, exposure to PTHrP (1-37) adsorbed in an implanted hydroxyapatite-based ceramic into a tibial defect in aging rats increased MKP1 and catalase gene expression in the healing bone area. Our findings demonstrate that PTHrP counteracts the pro-apoptotic actions of ROS by a mechanism dependent on MKP1-induced dephosphorylation of MAPKs in osteoblasts. J. Cell. Physiol. 232: 785-796, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, UAM and Red Temática de Investigación Cooperativa de Envejecimiento y Fragilidad (RETICEF)-Instituto de Salud Carlos III, Madrid, Spain.|Instituto de Medicina Molecular Aplicada (IMMA)-Universidad San Pablo CEU, Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Ardura
authors.affiliation: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, UAM and Red Temática de Investigación Cooperativa de Envejecimiento y Fragilidad (RETICEF)-Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Portal-Núñez
authors.affiliation: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, UAM and Red Temática de Investigación Cooperativa de Envejecimiento y Fragilidad (RETICEF)-Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Irantzu
authors.initials: I
authors.lastname: Castelbón-Calvo
authors.affiliation: Faculty of Biology, Animal Physiology II, Complutense University, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Martínez de Toda
authors.affiliation: Faculty of Biology, Animal Physiology II, Complutense University, Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: De la Fuente
authors.affiliation: Laboratorio de Metabolismo Mineral y Óseo, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, UAM and Red Temática de Investigación Cooperativa de Envejecimiento y Fragilidad (RETICEF)-Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Esbrit
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D044162:Parathyroid Hormone-Related Protein; D006861:Hydrogen Peroxide; D002374:Catalase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse