Orexin-A Reverse Bone Mass Loss Induced by Chronic Intermittent Hypoxia Through OX1R-Nrf2/HIF-1α Pathway

Abstract

Background: Recent studies suggest that there is a potential connection between obstructive sleep apnea (OSA) and osteoporosis through dysregulation of bone metabolism. Orexin-A, a neuroprotective peptide secreted by the hypothalamus, is at a lower level in the plasma of OSA patients, which regulates appetite, energy expenditure and sleep-wake states. However, the protective effect of orexin-A on bone metabolism in OSA is unclear. Purpose: To investigate whether the activation of OX1R by orexin-A can reverse bone mass loss induced by chronic intermittent hypoxia (CIH). Methods: Mice were randomly divided into the normoxia group and CIH group. Within the CIH or normoxia groups, treatment groups were given a subcutaneous injection of either orexin-A or saline vehicle once every day for 4 weeks and then femurs were removed for micro-CT scans. Histology and immunohistochemical staining were performed to observe and calculate the changes in femurs as a result of hypoxia. Cell immunofluorescence and immunohistochemical staining were used to detect the expression of orexin receptors in MC3T3-E1 cells or in bones. CCK-8 assay, ALP assay kit and alizarin red staining were used to detect the viability, alkaline phosphatase (ALP) activity, and capacity of mineralization, respectively. The effect of orexin-A on osteogenic differentiation of MC3T3-E1 cells was evaluated using qRT-PCR, Western blot and cell staining. Results: CIH led to a decrease in the amount and density of trabecular bone, downregulated OCN expression while increasing osteoclast numbers in femurs and inhibited the expression of RUNX2, OSX, OPN and Nrf2 in MC3T3-E1 cells. Orexin-A treatment alleviated these CIH-induced effects by combining to OX1R. The level of HIF-1α was elevated both in CIH and orexin-A treatment groups. Conclusion: CIH environment inhibits osteogenesis and orexin-A can reverse bone mass loss induced by CIH through OX1R-Nrf2 /HIF-1α pathway.

To investigate the mechanism of Yiwei Decoction in the treatment of premature ovarian insufficiency-related osteoporosis using transcriptomics, network pharmacology and molecular docking techniques

“…The hypothalamus is involved in the pathogenesis of osteoporosis. According to research, the hypothalamus is involved in bone metabolism in women with or without ovarian function loss 25 . Our study found that serum levels of GnRH and FSH were higher in POI rats than in normal rats, and that YWD could reduce serum levels of GnRH and FSH in POI rats.…”

Tempol attenuates chronic intermittent hypoxia-induced lung injury through the miR-145-5p/Nrf2 signaling pathway

“…There are many people with OSA in the world, and morbidity is rising and mostly occurs in middle-aged and elderly men (19). OSA is a complex somatic disease that has a significant impact on quality of life, mortality rate, and long-term cardiovascular outcomes (20).…”

The Role of Oxygen Homeostasis and the HIF-1 Factor in the Development of Neurodegeneration

“…Orexins play pivotal roles in regulating feeding behavior, energy balance, sleep-wake cycles, autonomic nervous system function, and neuronal survival [166]. Multiple studies have demonstrated that Orexin-A can upregulate the expression of HIF-1 by inhibiting VHL or E3 ubiquitin ligase activity [167][168][169]. In PD pathogenesis, mitochondrial dysfunction may lead to reduced oxygen consumption, thereby activating prolyl hydroxylase and decreasing HIF-1α levels, which subsequently reduces the expression of several transcription factors implicated in protecting the brain against oxidative stress.…”