Inflammation produced by senescent osteocytes mediates age-related bone loss

Abstract

PurposeThe molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs.MethodsWe collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR.ResultsThe GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H2O2-stimulated osteocyte-like cell MLO-Y4.ConclusionWith age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.

Down-expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenesis and accelerates age-related bone loss via PTEN/PI3K/AKT pathway

“…[25][26][27] In addition to exosome release, senescent osteocytes may also function in other ways, such as producing inflammation or SASP. 14,27 These possibilities were not explored in our study. Instead of isolating primary cells from aged mice, we induced senescence in MLO-Y4 cells through application of oxidative stress for our experiments.…”

“…11 Osteoblast function weakens with ageing, and limited bone formation or mineralization cannot fill the resorption cavity left by osteoclasts, resulting in bone mass loss and bone microarchitecture disorder. This process is known to be influenced by several factors, including the cellular microenvironment, hormone levels, inflammation, vascularization, oxidative stress, etc, [12][13][14][15] but the major regulators have yet to be determined.…”

Ferroptosis in Osteocytes as a Target for Protection Against Postmenopausal Osteoporosis

“…However, the role of osteocytes in postmenopausal osteoporosis still needs to be clarified. Recent studies have shown that damage to the function of osteocytes can lead to a variety of bone diseases, [ 17 , 18 , 78 ] but the changes experienced by osteocytes in postmenopausal osteoporosis patients have not been determined. In this study, we determined that osteocytes in postmenopausal osteoporosis experienced ferroptosis and that ferroptotic osteocytes affected the process of bone loss by regulating osteoclast‐mediated bone resorption.…”

Th17 Cell-Related Gene Biomarkers in Osteoporosis: Comprehensive Bioinformatics Analysis and In Vivo Validation

“…We found that these DETh17RGs are mainly enriched in Cellular senescence, Wnt signaling pathway, and Hippo signaling pathway. The study found that the senescence-associated secretory phenotype (SASP) produced by cell aging accumulates in the bone microenvironment, thereby further inducing bone aging [24]. The Wnt signaling pathway is a key signaling pathway for the osteogenic differentiation of MSCs, and the Wnt signaling pathway can activate β-catenin to regulate gene transcription, thereby promoting osteoblast proliferation and differentiation [25].…”