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JAK inhibition ameliorates bone destructions by simultaneously targeting mature osteoclasts and their precursor stages

ABSTRACT: JAK inhibition ameliorates bone destructions by simultaneously targeting mature osteoclasts and their precursor stages

PROVIDER: PRJNA794831 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17452791_1.fastq.gz	Fastqsanger.gz
	SRR17452791_2.fastq.gz	Fastqsanger.gz
	SRR17452792_1.fastq.gz	Fastqsanger.gz
	SRR17452792_2.fastq.gz	Fastqsanger.gz
	SRR17452793_1.fastq.gz	Fastqsanger.gz

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JAK inhibition ameliorates bone destructions by simultaneously targeting mature osteoclasts and their precursor stages

Project description:Inflammatory bone destruction was induced by locally injecting lipopolysaccharides into fluorescent reporter mice of mature osteoclasts or their precursors. These mice were treated with a JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and intravital imaging with multiphoton microscopy was conducted. We also investigated the molecular mechanism of the effects of the JAK inhibitor on osteoclasts by exhaustive RNA sequence analysis.

2023-03-05 | GSE193104 | GEO

JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors.

Project description:BackgroundRheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging.MethodsInflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts.ResultsThe JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions.ConclusionsThis is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.

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Chromatin Accessibility Profiling of Osteoclasts Precursor Cells

Project description:To understand the pathogenic mechanisms of bone erosion in rheumatoid arthritis (RA), we investigated osteoclast-specific epigenetic programs, RANKL-responsive super-enhancers (SEs) and SE-associated enhancer RNAs (SE-eRNAs) in human osteoclasts.

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Chromatin Accessibility Profiling of Osteoclasts Precursor Cells

Project description:Chromatin Accessibility Profiling of Osteoclasts Precursor Cells

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Effect of Hairy and Enhancer of Split 1 (HES1) activation on gene expression of mature osteoclasts

Project description:To investigate the role of HES1 in osteoclast differentiation and function, bone marrow-derived macrophages (BMMs) were derived from CtskCre/WT;RosaHes1 and control (Rosa[STOP]Hes1 ) mice and were differentiated into mature osteoclasts. We then performed gene expression profiling analysis using data obtained from RNA-seq of conrol and HES1-overexpressing osteoclasts.

2022-07-01 | GSE207120 | GEO

Murine Osteoclasts: Stat5 flox vs. Stat5 cKO

Project description:Transcriptional profiling of mouse osteoclasts comparing control osteoclasts from Stat5 flox mice with osteoclasts from Stat5 cKO mice. Two-condition experiment, Stat5 flox cells vs. Stat5 cKO cells

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Transcription profiling of mouse ERa abalated differentiated osteoclasts

Project description:Estrogen clearly prevents osteoporotic bone loss by attenuating bone resorption. The molecular basis of how this is accomplished, however, remains elusive. Here we report a critical role of osteoclastic ERa in mediating estrogen action on bone in females. We selectively ablated ERa in differentiated osteoclasts (ERa dOc/dOc). ERa dOc/dOc females, but not males, exhibited clear trabecular bone loss, similar to the osteoporotic bone phenotype in post-menopausal women. Recovery of bone loss by estrogen treatment of the ovariectomized ERa dOc/dOc females was ineffective in the trabecular areas of the long bones and lumbar vertebral bodies. Osteoclastic apoptosis, induced by estrogen, occurred simultaneously with up-regulation of Fas ligand (FasL) expression in intact trabecular bones of ERa +/+mice, but not in ERa dOc/dOc mice. ERa was also required for similar effects of estrogen and tamoxifen in cultured osteoclasts. These findings suggest that the osteoprotective actions of estrogen and SERMS are mediated at least in part through osteoclastic ERa in trabecular bone; and the life span of mature osteoclasts is regulated through activation of the Fas/FasL system. Experiment Overall Design: Wild type and osteoclast-specific Estrogen Receptor alpha knock-out mice were ovariectomized. The number of both genotypes of mice was eight. The mice of each genotypes were divided to vehicle control and estrogen treated group. Four hours after chemical treatment, the distal 5 mm of the left femurs were harvested after sacrificing by cervical dislocation and total RNAs were purified for Affymetix GeneChip microarray analysis without pooling. Therefore, this experiment consists of four groups with four replicates per group.

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Expression profile of osteoclasts treated with bisphosphonates

Project description:Bisphosphonates are the mainstay of therapy worldwide for osteoporosis. They inhibit the activities of the osteoclasts, the bone resorption cells. While bisphosphonates are known to block farnesyl pyrophsophate synthase to exert their anti-resorptive action, the detailed mechanism is not well understood. Examining the change in expression profile before and after bisphosphonate treatment in the osteoclasts might shed some light on the biological pathways that are perturbed. Osteoclastic precursor cells were treated with (or without) bisphosphonates (alendronate or risedronate) during their differentiation into mature osteoclasts.

2014-11-06 | E-GEOD-63009 | biostudies-arrayexpress