Functional change of mouse skeletal stem cells correlated with the progression of osteoporosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214645 | GEO | 2023/03/01
REPOSITORIES: GEO
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Project description:Background: Primary osteoporosis has increasingly become one of the risk factors affecting human health, and the clinical effect and action mechanism of traditional Chinese medicine in the treatment of primary osteoporosis have been widely studied. Previous studies have confirmed that in traditional Chinese medicine , Drynaria rhizome has a role in improving bone density. In this study, TMT-based proteomic analysis was conducted to derive potential targets for Drynaria rhizome treatment in postmenopausal osteoporosis. Methods: The model group (OVX) and experimental group (OVXDF) for menopausal osteoporosis were established using the universally acknowledged ovariectomy method, and the latter group received intragastric administration of 8.1 g /kg-1 of Drynaria rhizome for 12 weeks. After 12 weeks, femurs of rats selected for this study were examined with a bone mineral density (BMD) test, Micro-CT, ELISABiochemical testing, hematoxylin and eosin (HE) staining, and immunohistochemistry. A certain portion of the bone tissue was studied with a TMT-based proteomic analysis and functional and pathway enrichment analysis. Finally, key target genes were selected for Western blotting for validation. Results: The comparison of the OVXDF and OVX groups indicated that Drynaria rhizome could improve bone density. In the TMT-based proteomic analysis, the comparison of these two groups revealed a total of 126 differentially expressed proteins (DEPs), of which 62 were upregulated and 64 were downregulated. Further, by comparing the differential genes between the OVXDF and OVX groups and between the OVX and SHAM groups, we concluded that the 27 differential genes were significantly changed in the rats selected for the osteoporosis model after Drynaria rhizome intragastric administration. The gene ontology (GO) enrichment analysis of DEPs showed that molecular function was mainly involved in biological processes, such as glucose metabolism, carbohydrate metabolism, immune responses, and aging. A Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEPs revealed that multiple differential genes were enriched in the estrogen and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Relationships with nitrogen metabolism, glycerophospholipid metabolism, secretion systems, and tumor diseases were also observed. Western blotting was consistent with the analysis. Conclusions: We used TMT-based proteomics to analyze the positive effects of TCM Drynaria rhizome, which can regulate related proteins through the unique roles of multiple mechanisms, targets, and pathways. This treatment approach can regulate oxidative stress, improve lipid metabolism, reduce the inflammatory response mechanism, and improve bone density. These benefits highlight the unique advantages of TCM in the treatment of primary osteoporosis.
2024-10-17 | PXD035745 | Pride
Project description:Phosphorylation is important in skeletal muscle development, growth, regeneration, and contractile function. Alterations in the skeletal muscle phosphoproteome due to aging have been reported in males; however, studies in females are lacking. We have demonstrated that estrogen deficiency decreases muscle force which correlates with decreased myosin regulatory light chain phosphorylation. Thus, we questioned whether the decline of estrogen in females that occurs with aging might alter the skeletal muscle phosphoproteome. C57BL/6J female mice randomly assigned to a sham-operated (Sham) or ovariectomy (Ovx) group to investigate the effects of estrogen deficiency on skeletal muscle protein phosphorylation in a resting, non-contracting condition. After 16 weeks of estrogen deficiency, the tibialis anterior muscle was dissected and prepped for label-free nano-liquid chromatography tandem mass spectrometry phosphoproteomic analysis. We identified 4,780 phosphopeptides in tibialis anterior muscles of ovariectomized (Ovx) and Sham-operated (Sham) control mice. Further analysis revealed 647 differentially regulated phosphopeptides (Benjamini – Hochberg adjusted p-value < 0.05 and 1.5-fold change ratio) that corresponded to 130 proteins with 22 proteins differentially phosphorylated (3 unique to Ovx, two unique to Sham, six upregulated, and 11 downregulated). Differentially phosphorylated proteins associated with the sarcomere, cytoplasm, and metabolic and calcium signaling pathways were identified. Our work provides the first global phosphoproteomic analysis in females and how estrogen deficiency impacts the skeletal muscle phosphoproteome.
2022-09-28 | PXD035107 | Pride
Project description:Functional change of mouse skeletal stem cells correlated with the progression of osteoporosis
| PRJNA886451 | ENA
Project description:Fatty acid-binding protein 4 (FABP4), a key lipid protein in metabolism and inflammation, has been suggested to be linked to osteoporosis (OP), though direct evidence is scarce. Here, we present the first clear evidence of FABP4's significant role in OP, supported by clinical data and comprehensive in vivo and in vitro experiments. Elevated serum FABP4 in OP patients inversely correlates with bone mineral density (BMD), with similar trends observed in OVX mice. While FABP4 does not influence osteoblast differentiation, it promotes osteoclast formation and bone resorption. The FABP4 inhibitor BMS309403, with an IC50 of 0.89 μM, inhibits osteoclast differentiation by modulating calcium ions and suppressing the Ca2+-Calcineurin-NFATc pathway. Oral BMS309403 increased BMD in OVX mice, albeit less effectively than alendronate, whereas bone-targeted PLGA nanoparticles showed comparable efficacy to alendronate. This research identifies FABP4 as a promising therapeutic target for OP, with significant clinical implications.
2025-04-09 | GSE273951 | GEO
Project description:BMSC-derived exosomes from ovariectomized rats (OVX-Exo) and sham-operated rats (Sham-Exo) were co-cultured with bone marrow-derived macrophages to study their effects on osteoclast differentiation. Next-generation sequencing was utilized to identify the differentially expressed miRNAs (DE-miRNAs) in OVX-Exo and Sham-Exo, while target genes were analyzed using bioinformatics. The regulatory effects of miR-27a-3p and miR-196b-5p on osteogenic differentiation of BMSCs and osteoclast differentiation were verified by gain-of-function and loss-of-function analyses.Osteoclast differentiation was significantly enhanced in the OVX-Exo treatment group compared to the Sham-Exo group. Twenty DE-miRNAs were identified in OVX-Exo and Sham-Exo, among which miR-27a-3p and miR-196b-5p promoted the expressions of osteogenic genes in BMSCs. In contrast, knockdown of miR-27a-3p and miR-196b-5p increased the expressions of osteoclastic genes in osteoclasts. These 20 DE-miRNAs were found to target 11435 mRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these target genes were involved in several biological processes and osteoporosis-related signaling pathways.
2022-07-07 | GSE197085 | GEO
Project description:Postmenopausal osteoporosis is the main cause of fractures in women. Resistance exercise has a positive effect on bone mineral density in postmenopausal osteoporosis patients, but its mechanism is unclear. The purpose of this study was to explore the mechanism of resistance exercise in improving ovariectomized osteoporotic rats based on the transcriptome sequencing technique. Eighteen female Sprague-Dawley rats were randomly divided into the sham-operated group, the non-exercise group, and the resistance exercise group. The rat model of postmenopausal osteoporosis was established by bilateral ovariectomy. Ten weeks after the operation, the resistance exercise group received 2 weeks of adaptive training, and 12 weeks of resistance exercise began in the 13th week. The rats were trained 5 days per week, in 4 sets of 3 repetitions per day. After the intervention, all rats were sacrificed, and the body weight, bone mineral density, trabecular bone microarchitecture, and bone biomechanics were examined. At the same time, RNA-seq and enrichment analysis of gene ontology and Kyoto Encyclopedia of Genes and Genomes were performed on the left tibias, followed by Elisa and RT-qPCR verification. It had been found that resistance exercise can effectively counteract the weight gain of ovariectomized osteoporotic rats, and has a good effect on bone mineral density and trabecular bone microarchitecture. Enrichment analysis showed that regulation of gene expression and osteoclast differentiation is the most closely related biological process and signaling pathway shared by RE/Ovx and NE/Ovx groups. Our results revealed that resistance exercise can play a role in inhibiting osteoclast activation and preventing the enhancement of osteoclast bone resorption function in ovariectomized osteoporotic rats by inhibiting Fos/Fosb-regulated TRAP activation and relieving Calcr inhibition, which has important application value in preventing bone loss caused by estrogen deficiency.
2026-06-06 | GSE236613 | GEO
Project description:Purpose: Using RNA-sequencing technology to screen the effect of moderate-intensity treadmill exercise on the key genes that affect bone mass in the peripheral blood mononuclear cells (PBMCs) of ovariectomized (OVX) rats. Methods: Three-month-old female Sprague–Dawley rats of Specific Pathogen Free (SPF) grade were randomly divided into the sham operation (SHAM) group, OVX group, and OVX combined exercise (OVX+EX) group. The OVX+EX group performed moderate-intensity treadmill exercise for 17 weeks. Upon completion of these exercises, the body composition and bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry, and the bone microstructure of the femur was observed using micro-computed tomography scanning. PBMCs were collected from the abdominal aorta, and the differential genes were analyzed by transcriptome sequencing. The Metascape software was used for gene ontology and pathway enrichment analysis to further screen key genes. Results: 1. In the OVX group, the body weight and body fat content were significantly higher than in the SHAM group and the body muscle content and BMD were significantly lower. 2. The trabecular bone parameters in the OVX group were significantly lower than in the SHAM group, and they were significantly higher in the OVX+EX group than in the OVX group. When compared with the SHAM group, the microstructure of the distal femur trabecular in the OVX group was severely damaged, the trabecular bones were sparse, and there was a large gap between the trabecular bones. The number and continuity of the trabecular bones were higher in OVX+EX group than in the OVX group. 3. A Venn diagram showed that there were 58 common differential genes, with a fold change ≥2 and p value <0.05. and the differential genes were mainly enriched in the PI3K-Akt signaling pathway. Five key genes were screened including CCL2, Nos3, Tgfb3, ITGb4, and LpL. Conclusion: Moderate-intensity treadmill exercise may improve the body composition and bone mass of the OVX group by upregulating CCL2 and other genes of the PBMC. The results also showed that the PBMCs in the peripheral blood can be a useful tool for monitoring the effect of exercise on bone health in postmenopausal osteoporosis.
2021-11-17 | GSE184493 | GEO
Project description:PTH is an osteoanabolic for treating osteoporosis but its potency wanes. Disabling the transcription factor nuclear matrix protein 4 (Nmp4) in healthy, ovary-intact mice enhances bone response to PTH and bone morphogenetic protein 2 and protects from unloading-induced osteopenia. These Nmp4-/- mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8+ T cells. To determine whether the Nmp4-/- phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4-/- mice. To identify potential Nmp4 target genes, we performed bioinformatic/pathway profiling onNmp4chromatin immunoprecipitation sequencing (ChIP-seq) data. Mice (12 weeks old) were ovx or sham operated 4 weeks before the initiation of PTH therapy. Skeletal phenotype analysis included microcomputed tomography, histomorphometry, serum profiles, fluorescence-activated cell sorting and the growth/mineralization of cultured WT and Nmp4-/- bone marrow mesenchymal stem progenitor cells (MSPCs). ChIP-seq data were derived using MC3T3-E1 preosteoblasts, murine embryonic stem cells, and 2 blood cell lines. Ovx Nmp4-/- mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8+ T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4-/- MSPCs displayed enhanced proliferation and accelerated mineralization. ChIP-seq/gene ontology analyses identified target genes likely under Nmp4 control as enriched for negative regulators of biosynthetic processes. Interrogation of mRNA transcripts in nondifferentiating and osteogenic differentiating WT and Nmp4-/- MSPCs was performed on 90 Nmp4 target genes and differentiation markers. These data suggest that Nmp4 suppresses bone anabolism, in part, by regulating IGF-binding protein expression. Changes in Nmp4 status may lead to improvements in osteoprogenitor response to therapeutic cues.
2018-04-05 | GSE112693 | GEO
Project description:The loss of skeletal muscle strength mid-life in females is associated with the decline of estrogen. Here, we questioned how estrogen deficiency might impact the overall skeletal muscle phosphoproteome after contraction, as force production induces phosphorylation of several muscle proteins. Phosphoproteomic analyses of the tibialis anterior muscle after contraction in two mouse models of estrogen deficiency, ovariectomy (Ovariectomized [Ovx] vs Sham) and natural aging-induced ovarian senescence (Older Adult [OA] vs Young Adult [YA]), identified a total of 2,593 and 3,507 phosphopeptides in Ovx/Sham and OA/YA datasets, respectively. Further analysis of estrogen deficiency-associated proteins and phosphosites identified 66 proteins and 21 phosphosites from both datasets. Of these, 4 estrogen deficiency-associated proteins and 4 estrogen deficiency-associated phosphosites were significant and differentially phosphorylated or regulated, respectively. Comparative analyses between Ovx/Sham and OA/YA using Ingenuity Pathway Analysis (IPA) found parallel patterns of inhibition and activation across IPA-defined canonical signaling pathways and physiological functional analysis, which were similarly observed in downstream GO, KEGG, and Reactome pathway overrepresentation analysis pertaining to muscle structural integrity and contraction, including AMPK and calcium signaling. IPA Upstream regulator analysis identified MAPK1 and PRKACA as candidate kinases and calcineurin as a candidate phosphatase sensitive to estrogen. Our findings highlight key molecular signatures and pathways in contracted muscle suggesting that the similarities identified across both datasets could elucidate molecular mechanisms that may contribute to skeletal muscle strength loss due to estrogen deficiency.
2023-09-01 | PXD035171 | Pride
Project description:<p>Backround&Aim: Dysbiosis of gut microbiota is closely related to the pathogenesis of osteoporosis (OP). This study aimed to identify probiotic candidates and gut-derived metabolites capable of ameliorating osteoporosis via modulation of bone metabolism. </p><p>Methods: Ovariectomized (OVX) rats were used to model PMOP. Multi-omics analyses, including 16S rDNA sequencing, metagenomics, and untargeted metabolomics, were conducted to characterize gut microbiota(GM) and metabolic alterations following icariin (ICA) administration. Probiotic candidates enriched by ICA treatment were screened based on microbial and metabolic profiles. The effects of P. distasonis (LPD) were evaluated via oral gavage and fecal microbiota transplantation (FMT) in pseudo-germ-free OVX rats. Fecal samples from PMOP patients were analyzed using qPCR to assess LPD abundance. In vitro assays were performed to examine the osteogenic and anti-resorptive activities of glycerophospholipid metabolites derived from LPD.</p><p>Results: ICA administration improved bone microarchitecture and mechanical strength in OVX rats, restored intestinal barrier integrity, and altered GM composition. Multi-omics analysis identified Parabacteroides distasonis as a key bacterium enriched by ICA. Oral gavage of LPD and FMT from ICA-treated donors ameliorated bone loss in pseudo-germ-free OVX rats. Quantitative PCR of fecal samples confirmed reduced LPD abundance in PMOP patients. Metabolomic profiling revealed that ICA and LPD elevated circulating levels of phosphatidylcholine (PC), lysophosphatidylethanolamine (Lyso PE), and lysophosphatidylcholine (Lyso PC), which were positively correlated with bone formation markers. In vitro, these metabolites enhanced osteoblast differentiation and suppressed osteoclastogenesis.</p><p><strong>Conclusions: </strong>ICA exerts anti-osteoporotic effects via GM modulation, in part through enrichment of LPD and its glycerophospholipid metabolites. These findings highlight LPD as a promising probiotic candidate and support the therapeutic potential of targeting the gut-bone axis in PMOP.</p><p><br></p>
2025-08-01 | MTBLS12803 | MetaboLights