Ontology highlight
ABSTRACT:
PROVIDER: PRJNA268824 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1664815.fastq.gz | Fastqsanger.gz | |||
| SRR1664816.fastq.gz | Fastqsanger.gz | |||
| SRR1664817.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 3 of 3 |
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Project description:Osteoclasts are absorptive cells and play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic regulation of osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation during osteoclast formation. DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. DOT1L inhibition also increased osteoclast area and accelerated bone mass reduction in a mouse ovariectomy (OVX) model of osteoporosis. DOT1L inhibitors did not alter osteoblast differentiation in vitro and in vivo. Proteomics data, together with bioinformatics analysis, revealed that DOT1L inhibition altered reactive oxygen species (ROS) generation, autophagy activation, and cell fusion-related protein expression. ROS generation increased, and autophagy activation and cell migration ability enhancement were verified subsequently by flow cytometry and transwell migration assays. DOT1L inhibition increased NFATc1 nuclear translocation and NF-κB activation and strengthend osteoclast fusion and expression of resorption-related protein CD9, and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-mediated H3K79me2 epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease.
2018-01-24 | PXD006448 | Pride
Project description:Def6 suppresses osteoblast differentiation and mineralization both in vitro and in vivo. Def6 knockout (KO) mice exhibit osteoporotic phenotype with enhanced osteoclast formation. Osteoblast differentiation and bone formation are elevated as well in Def6 KO mice, indicating a high bone turnover rate that leads to bone loss in Def6 KO mice. Thus, lack of Def6 leads towards unbalanced activities between osteoclastic resorption and osteoblast mediated bone formation and disrupts normal bone remodeling. Def6 suppresses osteoblast differentiation via endogenous type I IFN-mediated feedback inhibition. These findings reveal that Def6 is a novel bone remodeling regulator that controls both osteoclast and osteoblast differentiation to maintain bone remodeling.
2021-01-04 | GSE148455 | GEO
Project description:Recent studies have provided links between glutamine metabolism and bone remodeling, but little is known about its role in primary osteoporosis progression. We aimed to determine the effects of inhibiting glutaminase (GLS) on two types of primary osteoporosis and elucidate the related metabolism. To address this issue, age-related and ovariectomy (OVX)-induced bone loss mouse models were used to study the in vivo effects of CB-839, a potent and selective GLS inhibitor, on bone mass and bone turnover. We also studied the metabolic profile changes related with aging and GLS inhibition in primary bone marrow stromal cells (BMSC) and that related with OVX and GLS inhibition in primary bone marrow-derived monocytes (BMM). Besides, we studied the possible metabolic processes mediating GLS blockade effects during aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation respectively via in vitro rescue experiments. We found that inhibiting GLS via CB-839 prevented OVX-induced bone loss while aggravated age-related bone loss. Further investigations showed that effects of CB-839 treatment on bone mass were associated with alterations of bone turnover. Moreover, CB-839 treatment altered metabolic profile in different orientations between BMSC of aged mice and BMM of ovariectomized mice. In addition, rescue experiments revealed that different metabolic processes mediated glutaminase blockade effects between aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation. Taken together, our data demonstrated the different outcomes caused by CB-839 treatment between two types of osteoporosis in mice, which were tightly connected to the suppressive effects on both aging-impaired osteoblastogenesis and OVX-enhanced osteoclastogenesis mediated by different metabolic processes downstream of glutaminolysis.
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Project description:Exosomes are secreted into the blood by various types of cells. These small vesicles are involved in bone remodeling by mediation of intercellular communication in osteoblasts, osteoclasts or their precursors. Alterations in exosomal proteins are related to the failure of bone remodeling, which results in progressive loss of bone mass and poor quality of bone structure. However, the molecular changes in serum-derived exosomes (SDEs) from patients with low bone density and their functions in bone remodeling remain to be fully elucidated. We present a quantitative proteomics analysis of exosomes purified from the serum of patients with osteoporosis/osteopenia and normal volunteers; these data are available via Proteome Xchange with the identifier PXDXXXXX. Overall, 1,371 proteins were identified with an overlap of 1,160 Gene IDs among the ExoCarta proteins. In vitro studies and bioinformatics analysis revealed that the main changes in the SDEs of osteoporosis patients were proteins playing critical roles in integrins-mediated mechanosensation and signaling cascades, which are implicated in aggravating the failure of bone remodeling, including the enhancement of osteoclast differentiation and inhibition of bone mineralization. In contrast, the main changes in SDEs of osteopenia patients were proteins known to facilitate both osteoclast differentiation and osteoblastic bone formation, which resulted in a compensatory elevation of bone remodeling. In addition, bioinformatics analysis indicated that SDEs from elderly volunteers mediate negative regulation of bone remodeling via selenium deficiency-associated oxidative stress. This information will be helpful in elucidating the pathophysiological functions of SDEs and aid in the development of osteoporosis diagnostics and therapeutics.
2018-04-09 | PXD006463 | Pride
Project description:Osteoporosis is characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-related bone formation, particularly increased osteoclastogenesis. However, the mechanisms by which epigenetic factors regulate osteoclast precursor differentiation during osteoclastogenesis remain poorly understood. Here, we show that the specific knockout of the chromatin remodeling factor Arid1a in bone marrow?derived macrophages (BMDMs) results in increased bone mass. The loss of Arid1a in BMDM inhibits cell?cell fusion and maturation of osteoclast precursors, thereby suppressing osteoclast differentiation. Mechanistically, Arid1a increases the chromatin access in the gene promoter region of sialic acid?binding Ig-like lectin 15 (Siglec15) by transcription factor Jun/Fos, which results in the upregulation of Siglec15 and promotion of osteoclast differentiation. However, the loss of Arid1a reprograms the chromatin structure to restrict Siglec15 expression in osteoclast precursors, thereby inhibiting BMDM differentiation into mature osteoclasts. Deleting Arid1a after ovariectomy (a model for postmenopausal bone loss) alleviated bone loss and maintained bone mass. In summary, epigenetic reprogramming mediated by Arid1a loss suppresses osteoclast differentiation and may serve as a promising therapeutic strategy for treating bone loss diseases.
2024-05-01 | GSE231933 | GEO
Project description:Exosomes are secreted into the blood by various types of cells. These small vesicles are involved in bone remodeling by mediation of intercellular communication in osteoblasts, osteoclasts or their precursors. Alterations in exosomal proteins are related to the failure of bone remodeling, which results in progressive loss of bone mass and poor quality of bone structure. However, the molecular changes in serum-derived exosomes (SDEs) from patients with low bone density and their functions in bone remodeling remain to be fully elucidated. We present a quantitative proteomics analysis of exosomes purified from the serum of patients with osteoporosis/osteopenia and normal volunteers; these data are available via Proteome Xchange with the identifier PXDXXXXX. Overall, 1,371 proteins were identified with an overlap of 1,160 Gene IDs among the ExoCarta proteins. In vitro studies and bioinformatics analysis revealed that the main changes in the SDEs of osteoporosis patients were proteins playing critical roles in integrins-mediated mechanosensation and signaling cascades, which are implicated in aggravating the failure of bone remodeling, including the enhancement of osteoclast differentiation and inhibition of bone mineralization. In contrast, the main changes in SDEs of osteopenia patients were proteins known to facilitate both osteoclast differentiation and osteoblastic bone formation, which resulted in a compensatory elevation of bone remodeling. In addition, bioinformatics analysis indicated that SDEs from elderly volunteers mediate negative regulation of bone remodeling via selenium deficiency-associated oxidative stress. This information will be helpful in elucidating the pathophysiological functions of SDEs and aid in the development of osteoporosis diagnostics and therapeutics.
2025-06-27 | MSV000098365 | MassIVE
Project description:Osteoclasts and osteoblasts play a critical role in bone remodeling, and their dysregulation leads to pathological bone loss. However, precise regulation of their differentiation remains not fully elucidated. This study investigates the role of transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and reduced bone resorption. Mechanististically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which then regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency also enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.
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Project description:Objective: To study the effects of Short Chain Fatty Acids (SCFAs) on arthritic bone remodeling. Methods: We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3Cstopfl/fl CD4Cre mice, with SCFA supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum-level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by bulk transcriptomics analysis. Results: The osteoporosis condition in R26STAT3Cstopfl/fl CD4Cre animals is attributed primarily to an expansion of osteoclast progenitor cells (OCPs), leading to robust osteoclast differentiation. We show that SCFA supplementation can rescue the osteoporosis phenotype in this model of PsA. Our in vitro experiments revealed an inhibitory effect of the SCFAs on osteoclast differentiation, even at very low serum concentrations. This suppression of osteoclast differentiation enabled SCFAs to impede osteoporosis development in R26STAT3Cstopfl/fl CD4Cre mice. Further interrogation revealed that bone marrow derived OCPs from diseased mice expressed a higher level of SCFA receptors than that of control mice and that the progenitor cells in the bone marrow of SCFA-treated mice presented a modified transcriptomic landscape, suggesting a direct impact by SCFAs on osteoclast progenitors. Conclusion: We demonstrated how gut microbiota-derived SCFAs can regulate distal pathology, i.e., osteoporosis, and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut-bone axis in these disorders.
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