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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. y Portal Núñez, Sergio y Castelbón Calvo, Irantzu y Martínez de Toda Cabeza, Irene y Fuente del Rey, Mónica de la y 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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URL Oficial: http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-4652



Resumen

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.


Tipo de documento:Artículo
Palabras clave:Estrés oxidativo; hormona paratiroidea; osteoporosis
Materias:Ciencias Biomédicas > Biología
Ciencias Biomédicas > Biología > Fisiología animal
Código ID:44342
Depositado:24 Aug 2017 08:22
Última Modificación:24 Aug 2017 10:37

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