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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.

Background Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is the main cause of sudden death in adolescents and athletes globally. Hypoxia and immune factors have been revealed to be related to the pathology of HCM. There is growing evidence of a role for hypoxia and inflammation as triggers and enhancers in the pathology in HCM. However, the role of hypoxia- and immune-related genes in HCM have not been reported. Methods Firstly, we obtained four HCM-related datasets from the Gene Expression Omnibus (GEO) database for differential expression analysis. Immune cells significantly expressed in normal samples and HCM were then screened by a microenvironmental cell population counter (MCP-counter) algorithm. Next, hypoxia- and immune-related genes were screened by the LASSO + support vector machine recursive feature elimination (SVM-RFE) and weighted gene co-expression network analysis (WGCNA). Single-gene enrichment analysis and expression validation of key genes were then performed. Finally, we constructed a competing endogenous RNA (ceRNA) network of key genes. Results In this study, 35 differentially expressed hypoxia genes were found. By using LASSO + SVM-RFE analysis, 10 more targets with differentially expressed hypoxia genes were identified. The MCP-count algorithm yielded five differentially expressed immune cells, and after assessing them for WGCNA characteristics, 612 immune genes were discovered. When hypoxia and immune genes were combined for cross-tabulation analysis, three hypoxia- and immune-related genes (ATP2A2, DDAH1, and OMA1) were identified. Conclusion Based on hypoxia characteristic genes, three key genes were identified. These were also significantly related to immune activation, which proves a theoretical basis and reference value for studying the relationship between HCM and hypoxia and immunity. Graphical Abstract