Estrogen prevents cellular senescence and bone loss through Usp10-dependent p53 degradation in osteocytes and osteoblasts: the role of estrogen in bone cell senescence

Estrogens play multiple roles in maintaining skeletal homeostasis by regulating many physiological processes in bone cells. Recently, cellular senescence in bone cells, especially in osteocytes, has been demonstrated to be a pivotal factor in bone loss. However, whether and how estrogen mediates cellular senescence in bone cells remains unknown. Here, we show that estrogen is negatively correlated with p53-related cellular senescence, primarily through the regulation of p53 protein levels, both in vivo and in vitro. Further study confirmed that estrogen attenuated the nuclear import of p53 and accelerated p53 degradation in osteocyte-like MLO-Y4 cells and osteoblastic MC3T3-E1 cells. A screen of p53-related ubiquitinating/deubiquitinating enzymes indicated that estrogen induced the degradation of p53 through the regulation of Usp10, a deubiquitinase that is directly linked to p53. Usp10 inhibition attenuated H2O2-induced senescence in MLO-Y4 cells, as indicated by p53/p21 quantification, a senescence-associated β-galactosidase (SA-β-gal) assay, and p53 localization visualization with a confocal microscope. Usp10 overexpression abolished the estrogen-mediated regulation of p53 and the downstream transcriptional gene p21. The injection of ovariectomized (OVX) mice with Spautin-1, a Usp10 inhibitor, inhibited the expression of p53 and the transcription of downstream senescence markers, as well as promoted bone mass recovery. Taken together, our study unveils the regulatory function of estrogen in the prevention of cellular senescence through the regulation of Usp10, thereby accelerating the degradation of senescent factor p53 and inhibiting its nuclear import.