Necrostatin-1 treatment inhibits osteocyte necroptosis and trabecular deterioration in ovariectomized rats.

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.