Effect of deletion of NELL2 on gene expression in calvarial preosteoblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE266198 | GEO | 2025/04/11
REPOSITORIES: GEO
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Project description:Neural EGFL-like 2 (NELL2) is a secreted protein known for its regulatory functions in the nervous and reproductive systems, yet its role in bone biology remains unexplored. In this study, we observed that the NELL2 levels were diminished in the serum of osteoporosis patients, as well as in the bone of aged and ovariectomized (OVX) mice. In vitro loss-of-function and gain-of-function studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from mesenchymal progenitor cells. In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in a low bone turnover phenotype characterized by decreased cancellous bone mass in mice. Mechanistically, we identified Fibronectin 1 (Fn1) as a potential receptor for NELL2. Specifically, NELL2 interacted with the FNI-type domain located at the C-terminus of Fn1. Moreover, we found that NELL2 activated the focal adhesion kinase (FAK)/AKT signaling pathway through Fn1/integrin β1 (ITGB1), leading to the promotion of osteogenesis and the inhibition of adipogenesis. Notably, administration of NELL2-AAV was found to ameliorate bone loss in OVX mice. These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis, suggesting its potential as a therapeutic target for managing osteoporosis.
2025-04-11 | GSE265936 | 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.
2024-06-17 | MTBLS9415 | MetaboLights
Project description:Effect of deletion of NELL2 on gene expression in calvarial preosteoblasts
| PRJNA1106360 | ENA
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:This a model from the article:
Parathyroid hormone temporal effects on bone formation and resorption.
Kroll MH. Bull Math Biol
2000 Jan;62(1):163-88 10824426
,
Abstract:
Parathyroid hormone (PTH) paradoxically causes net bone loss (resorption) when
administered in a continuous fashion, and net bone formation (deposition) when
administered intermittently. Currently no pharmacological formulations are
available to promote bone formation, as needed for the treatment of
osteoporosis. The paradoxical behavior of PTH confuses endocrinologists, thus, a
model bone resorption or deposition dependent on the timing of PTH
administration would de-mystify this behavior and provide the basis for logical
drug formulation. We developed a mathematical model that accounts for net bone
loss with continuous PTH administration and net bone formation with intermittent
PTH administration, based on the differential effects of PTH on the osteoblastic
and osteoclastic populations of cells. Bone, being a major reservoir of body
calcium, is under the hormonal control of PTH. The overall effect of PTH is to
raise plasma levels of calcium, partly through bone resorption. Osteoclasts
resorb bone and liberate calcium, but they lack receptors for PTH. The
preosteoblastic precursors and preosteoblasts possess receptors for PTH, upon
which the hormone induces differentiation from the precursor to preosteoblast
and from the preosteoblast to the osteoblast. The osteoblasts generate IL-6;
IL-6 stimulates preosteoclasts to differentiate into osteoclasts. We developed a
mathematical model for the differentiation of osteoblastic and osteoclastic
populations in bone, using a delay time of 1 hour for differentiation of
preosteoblastic precursors into preosteoblasts and 2 hours for the
differentiation of preosteoblasts into osteoblasts. The ratio of the number of
osteoblasts to osteoclasts indicates the net effect of PTH on bone resorption
and deposition; the timing of events producing the maximum ratio would induce
net bone deposition. When PTH is pulsed with a frequency of every hour, the
preosteoblastic population rises and decreases in nearly a symmetric pattern,
with 3.9 peaks every 24 hours, and 4.0 peaks every 24 hours when PTH is
administered every 6 hours. Thus, the preosteoblast and osteoblast frequency
depends more on the nearly constant value of the PTH, rather than on the
frequency of the PTH pulsations. Increasing the time delay gradually increases
the mean value for the number of osteoblasts. The osteoblastic population
oscillates for all intermittent administrations of PTH and even when the PTH
infusion is constant. The maximum ratio of osteoblasts to osteoclasts occurs
when PTH is administered in pulses of every 6 hours. The delay features in the
model bear most of the responsibility for the occurrence of these oscillations,
because without the delay and in the presence of constant PTH infusions, no
oscillations occur. However, with a delay, under constant PTH infusions, the
model generates oscillations. The osteoblast oscillations express limit cycle
behavior. Phase plane analysis show simple and complex attractors. Subsequent to
a disturbance in the number of osteoblasts, the osteoblasts quickly regain their
oscillatory behavior and cycle back to the original attractor, typical of limit
cycle behavior. Further, because the model was constructed with dissipative and
nonlinear features, one would expect ensuing oscillations to show limit cycle
behavior. The results from our model, increased bone deposition with
intermittent PTH administration and increased bone resorption with constant PTH
administration, conforms with experimental observations and with an accepted
explanation for osteoporosis.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Kroll MH. (2000) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230083 | BioModels
Project description:NELL2 is a cytoplasmic and secreted glycosylated protein with six epidermal growth factor-like domains. In animal models, Nell2 is predominantly expressed in neural tissues where it regulates neuronal differentiation, polarization, and axon guidance, but little is known about the role of NELL2 in human brain development. In this study, we show that rostral neural stem cells (rNSC) derived from human iPSC exhibit particularly strong NELL2 expression, and that NELL2 protein is enriched at the apical side of neural rosettes in hiPSC derived brain organoids. Following differentiation of human rostral NSC into neurons, NELL2 remains robustly expressed but changes its subcellular localization from >20 small cytoplasmic foci in NSC to 1-5 large peri-nuclear puncta per neuron. Unexpectedly, we discovered that in human brain organoids NELL2 is readily detectable in oligodendroglia and that the number of NELL2 puncta increases as oligodendrocytes mature. Artificial intelligence-based machine learning further predicts a strong association of NELL2 with multiple human white matter diseases, suggesting that NELL2 may possess yet unexplored roles in regulating oligodendrogenesis and/or myelination during human cortical development and maturation.
2021-12-13 | GSE190633 | GEO
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:Appropriate nutrition during early development is essential for optimal bone mass accretion; however, linkage between early nutrition, childhood bone mass and prevention of bone loss later in life has not been extensively studied. In this report, we have demonstrated several fundamental issues in the field. 1) A significant prevention of ovariectomy (OVX) -induced bone loss from adult rats can occur with only 14 days consumption of a blueberry-containing diet immediately prior to puberty. 2) The molecular mechanisms underlying these effects involve increased myosin production and preserved a shuttle for transcription factors such as Runx2 from cytoplasm to nucleolus which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence. 3) The effects of blueberry diet on preserving fidelity of osteoblast differentiation also overcome reduced osteoblast differentiation and activity due to OVX-induced degradation of collagen matrix. Bone quality was compared among casein control diet sham operated, casein diet ovariectomized, long term BB diet ovariectomized, and short term BB diet ovariectomized female rats
2012-06-30 | E-GEOD-30081 | biostudies-arrayexpress
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:Appropriate nutrition during early development is essential for optimal bone mass accretion; however, linkage between early nutrition, childhood bone mass and prevention of bone loss later in life has not been extensively studied. In this report, we have demonstrated several fundamental issues in the field. 1) A significant prevention of ovariectomy (OVX) -induced bone loss from adult rats can occur with only 14 days consumption of a blueberry-containing diet immediately prior to puberty. 2) The molecular mechanisms underlying these effects involve increased myosin production and preserved a shuttle for transcription factors such as Runx2 from cytoplasm to nucleolus which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence. 3) The effects of blueberry diet on preserving fidelity of osteoblast differentiation also overcome reduced osteoblast differentiation and activity due to OVX-induced degradation of collagen matrix.
2012-07-01 | GSE30081 | GEO