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Mechanical Loading remodels transcriptional regulation in Osteocytes through Nucleus translocation of NRF2 [ChIP-seq]

ABSTRACT: The mechano-responsiveness of osteocytes is critical for maintaining bone health, yet the molecular mechanisms underlying this process remain poorly understood. Here, we investigate the impact of mechanical loading on transcriptional and epigenetic remodeling in osteocytes. Using MLO-Y4 cells, we subjected osteocytes to mechanical loading and profiled their transcriptome and histone modifications. Our findings revealed significant transcriptional and epigenetic changes, with NRF2 emerging as a key regulator. We demonstrated that mechanical loading stabilizes NRF2 protein levels and promotes its nucleus translocation, leading to enhanced genomic binding of NRF2 and activation of its target genes. Further analysis confirmed cell type-specific functions of NRF2, with distinct binding profiles in osteocytes compared to astrocytes. These results highlight the pivotal role of NRF2 in the mechano-responsiveness of osteocytes. Unlike pharmacologic agents that stabilize NRF2, mechanical loading uniquely promoted NRF2 nucleus translocation and transcriptional activity. This underscores the irreplaceable role of mechanical stimuli, such as exercise, in promoting bone health. This study advances our understanding of osteocyte mechanotransduction and identifies potential therapeutic interventions for bone diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE273535 | GEO | 2025/04/03

REPOSITORIES: GEO

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Mechanical Loading remodels transcriptional regulation in Osteocytes through Nucleus translocation of NRF2 [RNA-seq]

Project description:The mechano-responsiveness of osteocytes is critical for maintaining bone health, yet the molecular mechanisms underlying this process remain poorly understood. Here, we investigate the impact of mechanical loading on transcriptional and epigenetic remodeling in osteocytes. Using MLO-Y4 cells, we subjected osteocytes to mechanical loading and profiled their transcriptome and histone modifications. Our findings revealed significant transcriptional and epigenetic changes, with NRF2 emerging as a key regulator. We demonstrated that mechanical loading stabilizes NRF2 protein levels and promotes its nucleus translocation, leading to enhanced genomic binding of NRF2 and activation of its target genes. Further analysis confirmed cell type-specific functions of NRF2, with distinct binding profiles in osteocytes compared to astrocytes. These results highlight the pivotal role of NRF2 in the mechano-responsiveness of osteocytes. Unlike pharmacologic agents that stabilize NRF2, mechanical loading uniquely promoted NRF2 nucleus translocation and transcriptional activity. This underscores the irreplaceable role of mechanical stimuli, such as exercise, in promoting bone health. This study advances our understanding of osteocyte mechanotransduction and identifies potential therapeutic interventions for bone diseases.

2025-04-03 | GSE273537 | GEO

Mechano-sensitive Gene Expression with RNA-Seq: Revisiting the Osteocytic Cell Response to Fluid Flow

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2017-07-23 | GSE70667 | GEO

Targeting long non-coding RNA H19 in Subchondral Bone Osteocytes Alleviates Cartilage Degradation in Osteoarthritis

Project description:Introduction: Emerging evidence suggests long non-coding RNA (lncRNA) H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biological function of H19 in OA subchondral bone remodeling and OA progression. Methods: Clinical joint samples and OA animal models induced by medial meniscus destabilization (DMM) surgery were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechano-response. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles in order to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment. Results: Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass with more H19 expressing osteocytes. On the contrary, osteocyte-specific deletion of H19 mice is less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechano-response through PI3K/AKT/GSK3 signals activation by EZH2-induced H3K27me3 regulation on PP2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype. Discussion: In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.

2025-03-05 | GSE254053 | GEO

Mechanical loading influences osteocytes and further regulates osteoblast metabolism and osteogenic differentiation(miRNA Array)

Project description:A previous study indicated that mechanical tensile strain of 2500 microstrain (με) at 0.5 Hz for 8 h promoted osteogenesis and corresponding mechanoresponsive microRNAs (miRs) were identified in osteoblasts. However, in osteocytes, it has not been identified which miRs respond to the mechanical strain, and it is not fully understood how the mechanoresponsive miRs regulate osteoblast differentiation. Mouse MLO-Y4 osteocytes were applied to the same mechanical tensile strain in vitro.MiR microarray and reverse transcription-quantitative polymerase chainreaction(RT-qPCR) assays were applied to select and validate differentially expressed miRs, and the target genes of these miRs were then predicted. In addition, the differentially expressed miRNAs in mechanically strained osteocytes in vitro were compared with those in treadmill exercise of the bone tissues .

2021-07-02 | GSE179199 | GEO

Whole gene expression data from osteocyte-like cell line MLO-Y4 under large gradient high magnetic field (LG-HMF)

Project description:osteocyte is the mechanosensor in bone, taking up pivotal position in mediating the mechano-induced bone remodeling. Dimagnetic levitation has been used to stimulating a reduced gravity environment for studing the effects of changed gravity to different organisms.we constructed a superconducting magnet based platform with a large gradient high magnetic field(LG-HMF),which can provide three apparent gravity levels (?-g,1-g and 2-g). osteocytes are sensetive to gravitational changes, our aim is to explore what responses do osteocytes exists under different gravitational environments in gene level, together with filtering the up- and down-regulated genes. mouse osteocyte-like cell line MLO-Y4 were cultured under three different apparent gravity levels (?-g,1-g and 2-g) and normal gravity environment (control) for 48 hours, after which total RNA was extracted . And then RNA samples hybridized on affymetrix microarrays to obtain the whole genome expression profiles. the aim that we selected 48 hours as the cell culture time was to make a comparison with our previous researches of osteocytes.

2015-02-02 | E-GEOD-62128 | biostudies-arrayexpress

Transcription profiling by array of mouse osteocyte MLO-Y4 cells treated with low doses of the nitrogen-containing bisphosphonates alendronate and risedronate

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2009-02-15 | E-MEXP-1470 | biostudies-arrayexpress

Osteoblast and Osteocyte Profiles at Different Cell-cummunication Status

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Osteocytes as main responders to Low Intensity Pulsed Ultrasound for the treatment of fracture healing

Project description:Skeletal tissue is known to respond to mechanical stress. Ultrasound stimulation is one of mechanical stress and low intensity pulsed ultrasound (LIPUS) devices have been clinically utilized to promote the fracture healing. However, it is still not clear which skeletal cells, especially osteocytes or osteoblasts, mainly respond to LIPUS stimulation and how they contribute to fracture healing. To examine that, we utilized medaka known to have bones without embedded osteocytes and zebrafish known to have bones with embedded osteocytes as an in vivo model. Interestingly, fracture healing was accelerated by ultrasound stimulation in zebrafish but not in medaka. To examine the molecular events induced by LIPUS stimulation in osteocyte, we performed RNA-sequencing with the murine long bone osteocyte Y4 (MLO-Y4) cell line exposed to LIPUS. 179 genes reacted to LIPUS stimulation and functional cluster analysis defined that several molecular signatures related in immunity, secretion and transcription. Especially, most of isolated transcription related genes were modulated by LIPUS also in vivo experiments using zebrafish. Target genes analysis showed that inflammatory response and bone formation in fracture healing could be transcriptionally regulated in osteocytes by LIPUS stimulation. Among these transcription genes, early growth response (Egr) 1,2, JunB, Forkhead box Q1 (FoxQ1) and nuclear factor of activated T cells (NFAT) c1 were not altered by LIPUS in medaka unlike zebrafish suggesting that these genes would be key transcriptional regulator of LIPUS-dependent fracture healing through osteocytes. In this study, we revealed bone-equipped osteocytes is necessary for LIPUS-induced promotion of fracture healing through the transcriptional control of target genes presumably to activate neighboring cells involved in fracture healing event.

2021-05-03 | GSE162674 | GEO

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Integrative transcriptomic and proteomic analysis of osteocytic cells exposed to fluid flow reveals novel mechano-sensitive signaling pathways

Project description:Osteocytes, positioned within boneâs interstitial space, are subject to fluid flow upon whole bone loading. Such fluid flow is widely theorized to be a mechanical signal transduced by osteocytes, initiating a poorly understood cascade of signaling events mediating bone metabolism. The objective of this study was to utilize high-throughput approaches to examine the time course of flow-induced changes in osteocyte gene transcript and protein levels. Microarray analysis demonstrated fluid flow regulation of genes consistent with known anabolic loading responses, including Ptgs2, NF-ÎºB inhibitors, MAP3 kinases, and Wnt/Î²-catenin pathway signaling molecules. However, two of the most highly up-regulated gene productsâCxcl1 and Cxcl2, confirmed by qPCRâhave not previously been reported to be responsive to fluid flow. Gene ontology analysis suggested a highly significant inflammatory and immune response, with cellular functions including trafficking, cell-to-cell signaling, and tissue development. Proteomic analysis of the same samples demonstrated greatest up-regulation of the ATP-producing enzyme NDK, calcium-binding Calcyclin, and G protein-coupled receptor kinase 6. An integrative pathway analysis merging fold changes in transcript and protein levels predicted signaling nodes not directly detected at the sampled time points, including STAT3 and c-Myc. These results extend our knowledge of the osteocytic response to fluid flow, most notably up-regulation of Cxcl1 and Cxcl2 as a possible paracrine agent for osteoblastic and osteoclastic recruitment. Osteocyte-like MLO-Y4 cells were subjected to 2 hours of 10 dyn/cm2 oscillating fluid flow in parallel-plate fluid flow chambers and harvested for analysis at 0, 2, 8, and 24 hours post-flow incubation. Parallel control samples from sham treated cells were also collected at each time point.

2013-07-01 | E-GEOD-42874 | biostudies-arrayexpress

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