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Objectives: oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (pTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The pTH counterpart in bone, which is the pTHrelated protein (pTHrp), displays osteogenic actions through both its n-terminal pTH-like region and the c-terminal domain. Methods: We examined and compared the antioxidant capacity of pTHrp (1-37) with the c-terminal pTHrp domain comprising the 107-111 epitope (osteostatin) in both murine osteoblastic Mc3T3-e1 cells and primary human osteoblastic cells. Results: We showed that both n- and c-terminal pTHrp peptides at 100 nM decreased reactive oxygen species production and forkhead box protein o activation following hydrogen peroxide (H2o2)-induced oxidation, which was related to decreased lipid oxidative damage and caspase-3 activation in these cells. This was associated with their ability to restore the deleterious effects of H2o2 on cell growth and alkaline phosphatase activity, as well as on the expression of various osteoblast differentiation genes. The addition of Rp-cyclic 3′,5′-hydrogen phosphorothioate adenosine triethylammonium salt (a cyclic 3',5'-adenosine monophosphate antagonist) and calphostin c (a protein kinase c inhibitor), or a pTH type 1 receptor antagonist, abrogated the effects of n-terminal pTHrp, whereas protein phosphatase 1 (an src kinase activity inhibitor), sU1498 (a vascular endothelial growth factor receptor 2 inhibitor), or an anti osteostatin antiserum, inhibited the effects of c-terminal pTHrp. Conclusion: These findings indicate that the antioxidant properties of pTHrp act through its n- and c- terminal domains and provide novel insights into the osteogenic action of pTHrp., RETICEF [FEDER “una manera de hacer Europa”], Ministerio de Economía y Competitividad. Programa Juan de la Cierva, Instituto de Salud Carlos III /Fundación para la Investigación Ósea y Metabolismo Mineral-FEIOMM, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub