SILAC analysis of long bone osteoblasts isolated from Tgif1+/+ and Tgif1-/- mice
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion ETD
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Osteoblast
DISEASE(S): Osteoporosis
SUBMITTER: 
Marcel Kwiatkowski
LAB HEAD: Eric Hesse
PROVIDER: PXD012303 | Pride | 2019-01-29
REPOSITORIES: Pride
Similar Datasets
Project description:Osteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although the mechanisms underlying this phenomenon are unclear. Here we identified a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a novel coupling factor that is involved in the PTH-mediated shift to the osteoblastic phase. SLPI was highly upregulated in osteoblasts by PTH, and genetic ablation of SLPI severely impaired PTH-induced bone formation. SLPI induction in osteoblasts enhanced osteoblast differentiation intracellularly and was also secreted extracellularly, attracting neighboring osteoclasts to suppress osteoclastic function. Intravital bone imaging revealed that the PTH-mediated association between osteoblasts and osteoclasts was disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI, a previously unrecognized bone-coupling factor, mediates the communication of osteoblasts with osteoclasts to promote PTH-induced bone formation.
2021-01-17 | GSE145462 | GEO
Project description:This a model from the article:
Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone.
Komarova SV.
Endocrinology.2005 Aug;146(8):3589-95.
15860557,
Abstract:
To restore falling plasma calcium levels, PTH promotes calcium liberation from bone. PTH targets bone-forming cells, osteoblasts, to increase expression of the cytokine receptor activator of nuclear factor kappaB ligand (RANKL), which then stimulates osteoclastic bone resorption. Intriguingly, whereas continuous administration of PTH decreases bone mass, intermittent PTH has an anabolic effect on bone, which was proposed to arise from direct effects of PTH on osteoblastic bone formation. However, antiresorptive therapies impair the ability of PTH to increase bone mass, indicating a complex role for osteoclasts in the process. We developed a mathematical model that describes the actions of PTH at a single site of bone remodeling, where osteoclasts and osteoblasts are regulated by local autocrine and paracrine factors. It was assumed that PTH acts only to increase the production of RANKL by osteoblasts. As a result, PTH stimulated osteoclasts upon application, followed by compensatory osteoblast activation due to the coupling of osteoblasts to osteoclasts through local paracrine factors. Continuous PTH administration resulted in net bone loss, because bone resorption preceded bone formation at all times. In contrast, over a wide range of model parameters, short application of PTH resulted in a net increase in bone mass, because osteoclasts were rapidly removed upon PTH withdrawal, enabling osteoblasts to rebuild the bone. In excellent agreement with experimental findings, increase in the rate of osteoclast death abolished the anabolic effect of PTH on bone. This study presents an original concept for the regulation of bone remodeling by PTH, currently the only approved anabolic treatment for osteoporosis.
The model reproduces Figures 1B and 2A of the reference publication. To obtain the figures 1B, the parameter g21 needs changes. To obtain the figures 1A, the parameters g21, g12 and k2 need to changed. For details look at the curation tab.
The initial concentration of Osteoclasts (x1) is corrected to 1.06066 from 10.06066.
This model was taken from the
CellML repository and automatically converted to SBML.
The original model was:
CellMLdetails
The original CellML model was created by:
Lloyd, Catherine, May
c.lloyd@auckland.ac.nz
The University of Auckland
The Bioengineering Institute
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.
For more information see the terms of use.
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.
2010-11-23 | BIOMD0000000279 | BioModels
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:The energetic costs of bone formation require osteoblasts to coordinate their activities with tissues, like adipose, that can supply fuel molecules. In the case of intermittent parathyroid hormone treatment (PTH), a strategy used to reduce fracture risk, bone formation is proceeded by a change in lipid homeostasis. To investigate the requirement for fatty acid oxidation by osteoblasts during PTH-induced bone formation, we subjected mice with osteoblast-specific deficiency of mitochondrial long-chain b-oxidation as well as mice with adipocyte-specific deficiency for the PTH receptor or adipose triglyceride lipase to an anabolic treatment regime. PTH increased b-oxidation by osteoblasts and the release of fatty acids from adipocytes, while the genetic mouse models were resistant to the hormone’s anabolic effect. Collectively, these data suggest that PTH’s anabolic actions requires coordinated signaling in bone as well as in adipose, wherein a lipolytic response liberates fatty acids that are oxidized by osteoblasts to fuel bone formation
2023-04-12 | GSE222173 | GEO
Project description:Bone is a dynamic organ in which bone formation mediated by osteoblasts balances against bone resorption mediated by osteoclasts to maintain bone homeostasis. With age, this balance gradually tilts toward bone resorption, leading to bone loss and osteoporosis. At the present study, the bone specimens from children (group A), middle-aged patients (group B), and older individuals (group C) were subjected to proteomics analysis by LC-MS/MS.
2023-02-01 | PXD039538 | Pride
Project description:Biased GPCR agonists are orthosteric ligands that possess pathway-selective efficacy, activating or inhibiting only a subset of the signaling repertoire of their cognate receptors. In vitro, D-Trp12,Tyr34-bPTH(7-34) (PTH-{beta}arr), a biased agonist for the type 1 parathyroid hormone receptor, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, both PTH-{beta}arr and the conventional agonist PTH(1-34) stimulate anabolic bone formation. To understand how two PTH1R ligands with markedly different in vitro efficacy could elicit similar in vivo responses, we analyzed transcriptional profiles from calvarial bone of mice treated for 8 weeks with vehicle, PTH-{beta}arr or PTH(1-34). Treatment of wild type mice with PTH-{beta}arr primarily affected pathways that promote expansion of the osteoblast pool, notably cell cycle regulation, cell survival and migration. These responses were absent in beta-arrestin2 null mice, identifying them as downstream targets of beta-arrestin2-mediated signaling. In contrast, PTH(1-34) primarily affected pathways classically associated with enhanced bone formation, including collagen synthesis and matrix mineralization. PTH(1-34) actions were less dependent on beta-arrestin2, as might be expected of a ligand capable of G protein activation. These results illustrate the uniqueness of biased agonism in vivo and demonstrate that functional selectivity can be exploited to change the quality of GPCR efficacy.
2013-03-07 | GSE35181 | GEO
Project description:Clinical investigations show that short-term treatment with gastric inhibitory polypeptide (GIP) acutely decreases serum markers of bone resorption and may increase bone formation. We report that the GIP receptor (GIPR) is expressed in human osteoclasts. Furthermore, GIP inhibits osteoclastogenesis, delays and inhibits bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways to impair nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) and nuclear factor-κB (NFκB). Human osteoblasts also express GIPR. Although GIP improves osteoblast survival via cAMP and Akt-mediated pathways, expression of osteoblast-specific genes including RUNX2 and BGLAP and bone formation is not changed by GIP. Treatment of co-cultures of osteoclasts and osteoblasts with GIP decreased bone resorption but did not change formation. Antagonizing the GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoblasts and osteoclasts. Clinical studies are needed to determine if longer-term GIPR activation uncouples bone resorption and formation and improves bone mass
2022-10-01 | GSE201100 | GEO
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:A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nmp4 respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. To address how loss of Nmp4 maximizes anabolic output we used RNA-seq and network analyses, along with biochemical and bone mechanical measurements to define this anti-anabolic axis. Several independent preparations of expanded mesenchymal stem/progenitor cells (MSPCs) were derived from individual Nmp4-/- and WT mice. The Nmp4-/- cells exhibited accelerated and enhanced mineralization. Loss of Nmp4 significantly altered the expression of over 5,000 genes. While Nmp4 status did not alter the mRNA expression of Runx2 and Sp7, key regulators of osteoblast differentiation, Nmp4-depletion enhanced expression of genes that drive osteogenesis and conversion to aerobic glycolysis, a key step in bone anabolism. Functional studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion. Several canonical pathways sensitive to Nmp4 status controlled protein production and delivery and as predicted the Nmp4-/- cells showed elevated collagen translation and secretion. Expression of matrix genes that contribute to bone material-level mechanical properties were elevated in Nmp4-/- cells. Mechanical analysis of femurs from Nmp4-/- mice treated with osteoporosis therapies resulted in enhanced bone material properties compared to WT mice. In conclusion, disabling Nmp4 converts the osteoblast into a super-secretor by metabolically reprogramming the cell to support the concomitant elevated matrix production and expansion of the cell’s delivery capacity. Resolving this pathway will guide advances in osteoporosis therapy.
2018-04-05 | GSE112694 | GEO
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