MMP14 cleaves PTH1R in the chondrocyte derived osteoblast lineage, curbing signaling intensity for proper bone anabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE222203 | GEO | 2023/03/13
REPOSITORIES: GEO
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Project description:To investigation the role of PTH and Kindlin-2 in bone development, we performed single-cell RNA-sequencing. From Con-veh, Con-PTH, cKO-veh, cKO-PTH, we profiled more than 20k single cells, including multi-potent mesenchymal stromal cells (MSC), osteoprogenitors, osteoblasts, chondrocytes, fibroblasts, endothelial cells, smooth muscle cells, skeletal muscle cells, pericytes, and schwann cells. We found proportion of part of these cells were significant altered by PTH or Kindlin-2 loss, especially for MSC, osteoblast, chondrocyte, and fibroblast. Transcriptomic analysis revealed gene expression was dramatically regulated by PTH or Kindlin-2 loss.
2020-10-01 | GSE150291 | GEO
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: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:Purpose: Identify PTH-responsive genes in MC3T3-E1 cells. The aim of the study is to identify novel gene targets that are reugulated by PTH signaling in bone, elicting its anabolic effect in osteoblasts. Methods: mRNA expression profiles were compared between Vehicle and PTH(1-34)-treated MC3T3-1 cells, in triplicates, using Illumina HiSeq 2000 PE100 sequncing. qPCR using Taqman probes were used to validate genes of interest. Results: Sequence reads per sample were mapped to the mouse genome (mm10) and differential expression of each gene was determined. Genes that showed differential expression between Vehicle vs PTH(1-34)-treated samples and has a relevant function in bone were further characterized by knockdown strategies in MC3T3-E1 cells. Conclusion: Our study have identified a list of novel genes regulated by PTH siganling. The characterization of their transcription and function in osteoblasts and osteocytes added to our knowledge of PTH signaling in bone and other skeletal tissues.
2020-07-14 | GSE154355 | GEO
Project description:Eric Hesse 9 Jan 2019, 17:34 (15 hours ago) to me, Hartmut Lieber Marcel, unten ist das abstract kopiert, reicht das? Lg, Eric Abstract Osteoporosis is caused by increased bone resorption and decreased bone formation. Intermittent administration of a fragment of Parathyroid hormone (PTH) activates osteoblast-mediated bone formation and is used in patients with severe osteoporosis. However, the mechanisms by which PTH elicits its anabolic effect are not fully elucidated. Here we show that the absence of the homeodomain protein TG-interacting factor 1 (Tgif1) impairs osteoblast differentiation and activity, leading to a reduced bone formation. Deletion of Tgif1 in osteoblasts and osteocytes decreases bone resorption due to an increased secretion of Semaphorin 3E (Sema3E), an osteoclast-inhibiting factor. Tgif1 is a PTH target gene and PTH treatment failed to increase bone formation and bone mass in Tgif1-deficient mice. Thus, our study identifies Tgif1 as a novel regulator of bone remodeling and an essential component of the PTH anabolic action. These insights contribute to a better understanding of bone metabolism and the anabolic function of PTH.
2019-01-29 | PXD012303 | Pride
Project description:Proctor2016 - Circadian rhythm of PTH and the
dynamics of signaling molecules on bone remodeling
This model is described in the article:
Simulated Interventions to
Ameliorate Age-Related Bone Loss Indicate the Importance of
Timing.
Proctor CJ, Gartland A.
Front Endocrinol (Lausanne) 2016; 7:
61
Abstract:
Bone remodeling is the continuous process of bone resorption
by osteoclasts and bone formation by osteoblasts, in order to
maintain homeostasis. The activity of osteoclasts and
osteoblasts is regulated by a network of signaling pathways,
including Wnt, parathyroid hormone (PTH), RANK
ligand/osteoprotegrin, and TGF-?, in response to stimuli, such
as mechanical loading. During aging there is a gradual loss of
bone mass due to dysregulation of signaling pathways. This may
be due to a decline in physical activity with age and/or
changes in hormones and other signaling molecules. In
particular, hormones, such as PTH, have a circadian rhythm,
which may be disrupted in aging. Due to the complexity of the
molecular and cellular networks involved in bone remodeling,
several mathematical models have been proposed to aid
understanding of the processes involved. However, to date,
there are no models, which explicitly consider the effects of
mechanical loading, the circadian rhythm of PTH, and the
dynamics of signaling molecules on bone remodeling. Therefore,
we have constructed a network model of the system using a
modular approach, which will allow further modifications as
required in future research. The model was used to simulate the
effects of mechanical loading and also the effects of different
interventions, such as continuous or intermittent
administration of PTH. Our model predicts that the absence of
regular mechanical loading and/or an impaired PTH circadian
rhythm leads to a gradual decrease in bone mass over time,
which can be restored by simulated interventions and that the
effectiveness of some interventions may depend on their
timing.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000612.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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.
2016-05-26 | BIOMD0000000612 | BioModels
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:Teriparatide (PTH(1-34)) and its analogs, PTHrP(1-36) and abaloparatide (ABL) have been used for the treatment of osteoporosis, but their efficacy over long-term use is significantly limited. The 3 peptides exert time- and dose-dependent differential responses in osteoblasts, leading us to hypothesize that they may also differentially modulate the osteoblast transcriptome. We show that treatment of mouse calvarial osteoblasts with 1 nM of the 3 peptides for 4 h results in RNA-Seq data with PTH(1-34) regulating 367 genes, including 194 unique genes; PTHrP(1-36) regulating 117 genes, including 15 unique genes; and ABL regulating 179 genes, including 20 unique genes. There were 83 genes shared among all 3 peptides. Gene ontology analyses showed differences in Wnt signaling, cAMP-mediated signaling, bone mineralization, morphogenesis of a branching structure in biological processes; receptor ligand activity, transcription factor activity, cytokine receptor/binding activity and many other actions in molecular functions. The 3 peptides increased Vdr, Cited1 and Pde10a mRNAs in a pattern similar to Rankl, i.e., PTH(1-34) > ABL > PTHrP(1-36). mRNA abundance of other genes based on gene/pathway analyses, including Wnt4, Wnt7, Wnt11, Sfrp4, Dkk1, Kcnk10, Hdac4, Epha3, Tcf7, Crem, Fzd5, Pp2r2a, and Dvl3 showed that some genes were regulated similarly by all 3 peptides; others were not. Further delineation of which signaling events are attributable to PTH(1-34), PTHrP(1-36) or ABL exclusively and which are shared among all 3 will help improve our understanding of the effects these peptides have on the osteoblast and lead to the refinement of PTH-derived treatments for osteoporosis.
2023-12-15 | GSE240235 | GEO
Project description:Kindlin-2 modulates PTH1R to regulate bone mass and PTH actions in bone
| PRJNA631725 | ENA