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Aging increases the levels of reactive oxygen species (ROS) that cause oxidative stress and induce osteoblast apoptosis. ROS modify several signaling responses, including mitogen\u2010activated protein kinase (MAPK) activation, related to cell survival. Both parathyroid hormone (PTH) and its bone counterpart, PTH\u2010related protein (PTHrP), can regulate MAPK activation by modulating MAPK phosphatase\u20101 (MKP1). Thus, we hypothesized that PTHrP might protect osteoblasts from ROS\u2010induced apoptosis by targeting MKP1. In osteoblastic MC3T3\u2010E1 and MG\u201063 cells, H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>triggered p38, JNK, ERK and p66<jats:sup>Shc<\/jats:sup>phosphorylation, and cell apoptosis. Meanwhile, PTHrP (1\u201037) rapidly but transiently increased ERK and Akt phosphorylation without affecting p38, JNK, or p66<jats:sup>Shc<\/jats:sup>activation. H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010induced p38 and ERK phosphorylation and apoptosis were both decreased by pre\u2010treatment with specific kinase inhibitors or PTHrP (1\u201037) in both osteoblastic cell types. These dephosphorylating and prosurvival actions of PTHrP (1\u201037) were prevented by a phosphatase inhibitor cocktail, the phosphatase MKP1 inhibitor sanguinarine or a MKP1 siRNA. PTHrP (1\u201037) promptly enhanced MKP1 protein and gene expression and MKP1\u2010dependent catalase activity in osteoblastic cells. Furthermore, exposure to PTHrP (1\u201037) adsorbed in an implanted hydroxyapatite\u2010based 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\u2010apoptotic actions of ROS by a mechanism dependent on MKP1\u2010induced dephosphorylation of MAPKs in osteoblasts. J. Cell. 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