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Parathyroid Hormone‐Related Protein Protects Osteoblastic Cells From Oxidative Stress by Activation of MKP1 Phosphatase
Author(s) -
Ardura Juan A.,
PortalNúñez Sergio,
CastelbónCalvo Irantzu,
Martínez de Toda Irene,
De la Fuente Mónica,
Esbrit Pedro
Publication year - 2017
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25473
Subject(s) - mapk/erk pathway , p38 mitogen activated protein kinases , phosphatase , microbiology and biotechnology , biology , oxidative stress , phosphorylation , kinase , protein kinase b , apoptosis , endocrinology , biochemistry
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, H 2 O 2 triggered p38, JNK, ERK and p66 Shc phosphorylation, and cell apoptosis. Meanwhile, PTHrP (1‐37) rapidly but transiently increased ERK and Akt phosphorylation without affecting p38, JNK, or p66 Shc activation. H 2 O 2 ‐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.