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Effects of Apigenin and Rutaecarpine on Gene Expression Profiling of Human BMSC-derived osteoblasts [Microarray]

ABSTRACT: Aging causes dysfunctional changes to the bone microenvironment that lead to osteoporosis development. Osteoporosis is a serious bone health issue that is characterized by decreased bone formation and increased bone resorption. The aim of this study is to evaluate the effects of natural compounds, Apigenin and Rutaecarpine on osteoblast differentiation and examine if Apigenin and Rutaecarpine can rescue osteogenesis in aging-context. Using human bone marrow stromal cell line (hBMSCs) and primary cells obtained from young and aged women, we showed that Apigenin and Rutaecarpine are potent in inducing osteoblast differentiation and mineralization. These compounds were able to reduce senescence along with their impacts on suppressing oxidative stress and inflammation, which both contribute to aging and bone metabolic dysfunctions. Our microarray-based transcription profiling of hBMSC-derived osteoblasts treated with either 1 µM of Apigenin or Rutaecarpine during osteoblast differentiation for 21 days revealed distinct impacts of Apigenin and Rutaecarpine on different genes including those involved in bone metabolism and skeletal system development. Additionally, Ex-vivo organotypic embryonic chick-femur culture model was used to determine the osteogenic effects of Apigenin and Rutaecarpine. The average bone volume and cortical thickness of these chick femurs were both increased significantly by Apigenin and Rutaecarpine. Collectively, our study provides a novel insight for developing therapeutic strategies using natural compounds to combat aging and its effect on bone health.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252845 | GEO | 2024/03/20

REPOSITORIES: GEO

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Project description:Age is the primary risk factor for many chronic diseases and cognitive decline during brain aging may increase dementia risk. Hallmarks of brain aging including neuronal dysfunction and glial contribute to reduced cognitive function, and there is a persistent lack of effective treatments. Bioactive plant compounds called “nutraceuticals” can target age-related cellular processes and may protect cognitive function. Apigenin is a flavone found in plants such as chamomile and can inhibit hallmarks of aging such as cellular senescence, mitochondrial dysfunction, and impaired proteostasis. However, the underlying mechanisms of apigenin in the brain are not fully understood. Here, we characterized brain transcriptome changes in young and old mice given apigenin in drinking water and examined potential mechanisms in human astrocytes. Consistent with previous studies, we observed improved novel object recognition in old mice treated with apigenin versus old controls. Transcriptome analyses in old controls found differentially expressed genes related to immune responses, inflammation, and cytokine regulation versus young. Fewer differences were observed in old apigenin-treated versus old controls, but these changes were related to development, behavior, and antiviral responses. The majority of upregulated genes in old mice were downregulated with apigenin treatment and associated with immune responses. Similarly, the genes that were reduced with aging, but increased in old apigenin-treated mice were related to pathways important for neurological function/disease, cellular maintenance, and homeostatic signaling. We also found that glial cells drove the majority of the transcriptome differences with aging and apigenin-treatment. To explore the mechanism of action for apigenin in glial cells, we treated replicatively aged astrocytes with apigenin and observed reduced markers of inflammation and cellular senescence. Collectively, our data support the role of apigenin as a protector of cognitive and neuronal function protectant through the suppression of neuroinflammatory genes and proteins and may be especially important in non-neuronal cells.

Project description:Introduction: There is a clinical need for developing systemic transplantation protocols for use of human skeletal stem cells (also known bone marrow stromal stem cells) (hBMSC) in tissue regeneration. In systemic transplantation studies, only a limited number of hBMSC home to injured tissues suggesting that only a subpopulation of hBMSC possess âhomingâ capacity. Thus, we tested the hypothesis that a subpopulation of hBMSC defined by ability to form heterotopic bone in vivo, is capable of homing to injured bone. Methods: We tested ex vivo and in vivo homing capacity of a number of clonal cell populations derived from telomerized hBMSC (hBMSC-TERT) with variable ability to form heterotopic bone when implanted subcutaneously in immune deficient mice. In vitro transwell migration assay was used and in vivo homing ability to bone fractures in mice was visualized by bioluminescence imaging (BLI). In order to identify the molecular phenotype associated with enhanced migration, we carried out comparative DNA microarray analysis of gene expression of hBMSC-derived high bone forming (HBF) clones versus low bone forming (LBF) clones. Results: In this study, clonal cell populations forming in vivo bone were shown to exhibit higher ex vivo transwell migration and following intravenous infusion, enhanced in vivo homing ability to bone fractures. Comparative microarray analysis of LBF versus HBF clones identified a significant enrichment of gene categories of cell chemo-attraction, adhesion and migration. Among these genes, platelet-derived growth factor receptor (PDGF-R) Î± and Î² were highly expressed in HBF clones. Further studies showed that the chemoattractive effects of PDGF in vitro was more enhanced in HBF clones compared to LBF clones and this effect was abolished in presence of a PDGFR-Î²-specific inhibitor: SU-16f. Sorted PDGFR-Î²+ cells from LBF clones showed that the PDGFR-Î²+ enriched cell population exhibited strong chemoattractance towards PDGF. Conclusion: Our data demonstrate phenotypic and molecular association between in vivo bone formation and migratory capacity of hBMSC. PDGFR-Î² can be used as a potential marker for the prospective selection of hBMSC populations with high migration and bone formation capacities suitable for clinical trials for enhancing bone regeneration. Total RNA obtained from telomerized human bone marrow derived mesenchymal stromal cells (T4P38a) with high in vivo bone forming capacity and (T4P74a) with low bone forming capacity and three single cell clones with high bone forming capacities (DD8, AD10 and BB10) and three clones with low bone forming capacities (CF1, CB4 and CD4). All cells were cultured under standard conditions and RNAs were isolated at baseline with no induction. each sample was represented in doublicate as a and b.

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Effects of Apigenin and Rutaecarpine on Gene Expression Profiling of Human BMSC-derived osteoblasts [Microarray]

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