VSIG4 inhibits RANKL-induced osteoclastogenesis by suppressing Nrf2-mediated reactive oxygen species production
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ABSTRACT:
PROVIDER: PRJNA1039710 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26803487_1.fastq.gz | Fastqsanger.gz | |||
| SRR26803487_2.fastq.gz | Fastqsanger.gz | |||
| SRR26803488_1.fastq.gz | Fastqsanger.gz | |||
| SRR26803488_2.fastq.gz | Fastqsanger.gz | |||
| SRR26803489_1.fastq.gz | Fastqsanger.gz |
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Project description:Osteoporosis is a common systemic skeletal disorder especially in postmenopausal women due to excessive production and activation of osteoclasts. However, current anti-osteoporotic drugs used in clinical practice may cause some side effects. Thus, it is necessary to further explore the potential mechanisms regulating the differentiation of osteoclast and develop novel targets for the treatment of osteoporosis. In our study, we found that VSIG4 exhibited the most significant decline among VSIG family members. Overexpression of VSIG4 significantly inhibited RANKL-induced osteoclastogenesis and bone resorption function. Mechanismly, the western blot and immunofluorescence results also showed that overexpression of VSIG4 attenuated the expression of osteoclast marker genes and the activation of MAPK and NF-κB signaling pathways. We found that overexpression of VSIG4 could suppress the generation of reactive oxygen species (ROS) and activate the expression of Nrf2 and its downstream antioxidant enzymes. ML385, a potent Nrf2 inhibitor, was found to reverse the inhibitory impact of VSIG4 on osteoclast differentiation. Consistently, overexpression of VSIG4 also rescued OVX-induced bone loss and attenuated the activation of osteoclasts in vivo. Taken together, our results indicated that VSIG4 could be an novel target to address postmenopausal osteoporosis by suppressing osteoclast formation via regulation of Nrf 2-mediated ROS generation.
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Project description:To screen for altered gene expression during osteoclastogenesis, BMM cells treated with RANKL or RANKL+LE were subjected to gene expression profiling.
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Project description:Purpose: Among the diverse cytokines involved in osteoclast differentiation, IL-3 has been shown to inhibit RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. In the present study, we demonstrate that IL-3 activation of STAT5 inhibits RANKL-induced osteoclastogenesis through the induction of Id genes. Methods: To investigate the effect of STAT5 on osteoclast differentiation and IL-3-mediated inhibition of osteoclast differentiation, bone marrow derived macrophages isolated from STAT5 wild-type (Stat5fl/fl) or STAT5 cKO (STAT5;MX1-Cre) were differentiated to osteoclast in the presence of M-CSF and RANKL with or without IL-3; and bone marrow derived macrophges from STAT5 wild-type and STAT5 cKO were overexpressed with PMX-FIG (control) or STAT5A1*6 (constitutively active form of STAT5A) and differentiated to osteoclast. To analyze bone phenotype, femurs and tibiae of 16 week-old STAT5 wild-type and STAT5 cKO were subjected to micro CT analysis and histomorphometry, respectively. Results: Overexpression of STAT5 inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate either expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting that STAT5 plays an important role in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated expression of the Id1 and Id2 genes, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Moreover, micro-computed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in STAT5 conditional knockout mice than in wild-type mice in a RANKL injection model. Conclusion: Taken together, our results suggest that STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis through Id gene expression. Examination of 4 different combination of osteoclast differentiation condition of bone marrow derived macrophages.
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Project description:GDF11 treatment leads to bone loss in mice and strongly stimulates RANKL-induced osteoclastogenesis of bone marrow-derived macrophages (BMMs) in vitro. We used microarrays to identified distinct classes of up-regulated genes in BMMs after GDF11 treatment. Mouse BMMs were treated with or without GDF11 for RNA extraction and and hybridization on Affymetrix microarrays
2016-07-21 | E-GEOD-84609 | biostudies-arrayexpress
Project description:GDF11 treatment leads to bone loss in mice and strongly stimulates RANKL-induced osteoclastogenesis of bone marrow–derived macrophages (BMMs) in vitro. We used microarrays to identified distinct classes of up-regulated genes in BMMs after GDF11 treatment.
2016-07-21 | GSE84609 | GEO
Project description:To screen for altered gene expression during osteoclastogenesis, BMM cells treated with RANKL or RANKL+LEA were subjected to gene expression profiling.
2020-02-24 | GSE142866 | GEO
Project description:Purpose: Among the diverse cytokines involved in osteoclast differentiation, IL-3 has been shown to inhibit RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. In the present study, we demonstrate that IL-3 activation of STAT5 inhibits RANKL-induced osteoclastogenesis through the induction of Id genes. Methods: To investigate the effect of STAT5 on osteoclast differentiation and IL-3-mediated inhibition of osteoclast differentiation, bone marrow derived macrophages isolated from STAT5 wild-type (Stat5fl/fl) or STAT5 cKO (STAT5;MX1-Cre) were differentiated to osteoclast in the presence of M-CSF and RANKL with or without IL-3; and bone marrow derived macrophges from STAT5 wild-type and STAT5 cKO were overexpressed with PMX-FIG (control) or STAT5A1*6 (constitutively active form of STAT5A) and differentiated to osteoclast. To analyze bone phenotype, femurs and tibiae of 16 week-old STAT5 wild-type and STAT5 cKO were subjected to micro CT analysis and histomorphometry, respectively. Results: Overexpression of STAT5 inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate either expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting that STAT5 plays an important role in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated expression of the Id1 and Id2 genes, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Moreover, micro-computed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in STAT5 conditional knockout mice than in wild-type mice in a RANKL injection model. Conclusion: Taken together, our results suggest that STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis through Id gene expression.
2016-08-03 | GSE76988 | GEO
Project description:Under physiological conditions, osteoclasts (OCs) are generated from monocytic osteoprecursors under the stimulation of RANKL and M-CSF, requiring co-stimulatory signals from Fc receptor common γ chain (FcRγ) or DNAX-activated protein 12. It has been proposed that immune complexes (ICs) directly potentiate RANKL-mediated osteoclastogenesis by triggering FcγR-coupled Fcγ receptors (FcγRs), thereby linking IC accumulation and pathological osteolysis under various disease conditions. However, whether ICs possess pro-osteoclastogenic potential independent of RANKL is unknown. Here we demonstrate that IgG ICs alone can drive the differentiation of human blood monocytes into nonclassical OCs (NOCs) phenotypically and functionally distinguishable from RANKL-induced classical OCs (COCs). This novel noncanonical osteoclastogenesis pathway is triggered by full crosslinking of human FcγRIIa (hFcγRIIa), or co-ligation of hFcγRIIa and TLR4, and signals through the Src family kinase-STAT5 axis without inducing the expression of NFATc1, a master transcription factor for the previously described osteoclastogenesis pathways. Surprisingly, IgG ICs strongly overrule the generation of COCs driven by RANKL in vitro. More importantly, TRAP+ OCs found in the inflammatory joint tissues of hFcγRIIa-transgenic mice with collagen-induced arthritis bear the NFATc1- phenotype. Our results unmask the “double faces” of IgG ICs in health and disease, and suggest a novel and important pathway for ICs contributing to pathological bone erosion in inflammatory arthritis.
2019-08-15 | GSE135821 | GEO
Project description:Clarification of the mechanisms underlying osteoclast differentiation enable us to understand the physiology of bone metabolism as well as the pathophysiology of bone diseases, such as osteoporosis. Recently, it has been reported that epigenetics can determine the cell fate and regulate cell type specific gene expression. However, little is known about epigenetics during osteoclastogenesis. To reveal a part of epigenetics, especially focused on chromatin dynamics, during early osteoclastogenesis and identify novel transcription factors involved in osteoclastogenesis, we investigated genome-wide analysis of open chromatin during receptor activator of nuclear factor-M-NM-:B ligand (RANKL)-induced osteoclastogenesis using DNase I hypersensitive sites sequencing (DNase-seq). DNase-seq was performed using the extracted nuclei obtained from RAW264 cells treated with or without RANKL for 24 hours, followed by several bioinformatic analyses. DNase I hypersensitive sites (DHSs) during RANKL-induced osteoclastogenesis were dynamically changed and accumulated in promoter regions, although the distributions of DHSs among cis-regulatory DNA regions were identical regardless of RANKL stimulation. Motif discoveries from DHSs successfully identified well-known osteoclastogenic transcription factors such as Jun, CREB1, FOS, ATF2 and ATF4, but also novel transcription factors for osteoclastogenesis such as Zscan10, Atf1 Nrf1 and Srebf2. siRNA knockdown of these identified novel transcription factors impaired osteoclastogenesis. Taken together, DNase-seq can be a useful tool for comprehension of epigenetics, especially chromatin dynamics during osteoclastogenesis and for identification of novel transcription factors involved in osteoclastogenesis. This study may reveal underlying mechanisms that determine cell-type specific differentiation of bone cells and may lead to investigate novel therapeutic targets for osteoporosis. Examination of genome-wide DNase Hypersensitive Sites in differentiated and undifferentiated RAW264 cells.
2014-11-05 | E-GEOD-54139 | biostudies-arrayexpress