Abstract
Age-related bone loss is associated with an increased oxidative stress which is worsened by estrogen fall during menauposis. This observation has drawn attention to autophagy, a major cellular catabolic process, able to alleviate oxidative stress in osteoblasts (OB) and osteocytes (OST), two key bone cell types. Moreover, an autophagy decline can be associated with aging, suggesting that an age-related autophagy deficiency in OB and/or OST could contribute to skeletal aging and osteoporosis onset.In the present work, autophagy activity was analyzed in OST and OB in male and female mice according to their age and hormonal status. In OST, autophagy decreases with aging in both sexes. In OB, although a 95% decrease in autophagy is observed in OB derived from old females, this activity remains unchanged in males. In addition, while ovariectomy has no effect on OB autophagy levels, orchidectomy appears to stimulate this process. An inverse correlation between autophagy and the oxidative stress level was observed in OB derived from males or females. Finally, using OB-specific autophagy-deficient mice, we showed that autophagy deficiency aggravates the bone loss associated with aging and estrogen deprivation.Taken together, our data indicate that autophagic modulation in bone cells differs according to sex and cell type. The lowering of autophagy in female OB, which is associated with an increased oxidative stress, could play a role in osteoporosis pathophysiology and suggests that autophagy could be a new therapeutic target for osteoporosis in women.
Highlights
The coordinated action of osteoblasts (OB), the cells responsible for bone formation, and osteoclasts (OC), the cells specialized for bone resorption, ensures bone remodeling which is under the control of osteocytes (OST), the multifunctional mechanosensing cells embedded in the bone matrix [1]
A 70% decrease in LC3-II protein levels was observed in old female mice compared to the young, suggesting that aging induces an autophagy decline in OST both in male and female mice (Figure 1B)
OCX had no effect on OST autophagy (Figure 1C), our results suggest that OVX induced an increase in OST autophagic activity (Figure 1D)
Summary
The coordinated action of osteoblasts (OB), the cells responsible for bone formation, and osteoclasts (OC), the cells specialized for bone resorption, ensures bone remodeling which is under the control of osteocytes (OST), the multifunctional mechanosensing cells embedded in the bone matrix [1]. The remodeling process is highly active throughout life and perturbation of this process can lead to many bone metabolic defects including osteoporosis (OP). Age-related bone loss is associated with an increased oxidative stress that is worsened by estrogen fall during menauposis in women [4, 5]. This observation has drawn attention to autophagy, a major degradation pathway able to limit oxidative stress through the elimination of dysfunctional mitochondria [6, 7]. We have used OB-specific autophagy-deficient mice to analyze how autophagy defect can affect bone mass in old ovariectomized mice
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