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Parathyroid Hormone-Related Protein Protects Osteoblastic Cells From Oxidative Stress by Activation of MKP1 Phosphatase

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Ardura, Juan A. and Portal Núñez, Sergio and Castelbón Calvo, Irantzu and Martínez de Toda Cabeza, Irene and Fuente del Rey, Mónica de la and Esbrit, Pedro (2017) Parathyroid Hormone-Related Protein Protects Osteoblastic Cells From Oxidative Stress by Activation of MKP1 Phosphatase. Journal of Cellular Physiology, 232 (4). pp. 785-796. ISSN 0021-9541

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Official URL: http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-4652



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, H2 O2 triggered p38, JNK, ERK and p66Shc phosphorylation, and cell apoptosis. Meanwhile, PTHrP (1-37) rapidly but transiently increased ERK and Akt phosphorylation without affecting p38, JNK, or p66Shc activation. H2 O2 -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.


Item Type:Article
Uncontrolled Keywords:Estrés oxidativo; hormona paratiroidea; osteoporosis
Subjects:Medical sciences > Biology
Medical sciences > Biology > Animal physiology
ID Code:44342
Deposited On:24 Aug 2017 08:22
Last Modified:24 Aug 2017 10:37

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