title: Necrostatin-1 treatment inhibits osteocyte necroptosis and trabecular deterioration in ovariectomized rats.
abstract: Estrogen (E2) deficiency has been associated with accelerated osteocyte apoptosis. Our previous study showed necroptosis accelerated the loss of osteocytes in E2 deficiency-induced osteoporosis in rats in addition to apoptosis, but the mechanism involved remains. Necroptosis is a caspase-independent form of programmed cell death. In the necroptosis pathway, receptor interaction proteins 1 and 3 (RIP1/3) play vital roles. Necrostatin-1 (Nec-1) has been confirmed to be a specific inhibitor of necroptosis. However, the effect of Nec-1 on postmenopausal osteoporosis remains ambiguous. The aim of this study was to investigate the effect of Nec-1 on osteocytes in ovariectomized (OVX) rats. We found that an increased number of necroptotic osteocytes was related to the production of tumor necrosis factor-alpha (TNF-α) in OVX rats. Treatment with Nec-1 significantly decreased RIP1 and RIP3 expression in OVX rats and inhibited osteocyte necroptosis induced by TNF-α in vitro. Both E2 and Nec-1 treatment markedly ameliorated trabecular bone deterioration. Nec-1 also significantly elevated the levels of bone formation markers and decreased bone resorption markers. These data suggest that the role of Nec-1 on alleviating bone loss might be associated with Nec-1 restraining TNF-α-induced osteocyte necroptosis in rats with E2 deficiency-induced osteoporosis. This process may represent a novel therapeutic strategy for the treatment of postmenopausal osteoporosis.
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Hongwang
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Weikang
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Shiyang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Dianming
authors.initials: D
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007093:Imidazoles; D007211:Indoles; C507699:necrostatin-1