SLPI is a novel bone-coupling factor that controls parathyroid hormone-induced bone formation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145462 | GEO | 2021/01/17
REPOSITORIES: GEO
Similar Datasets
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:This a model from the article:
Modeling the interactions between osteoblast and osteoclast activities in bone remodeling.
Lemaire V, Tobin FL, Greller LD, Cho CR, Suva LJ.
J Theor Biol.2004 Aug 7;229(3):293-309.
15234198,
Abstract:
We propose a mathematical model explaining the interactions between osteoblasts and osteoclasts, two cell types specialized in the maintenance of the bone integrity. Bone is a dynamic, living tissue whose structure and shape continuously evolves during life. It has the ability to change architecture by removal of old bone and replacement with newly formed bone in a localized process called remodeling. The model described here is based on the idea that the relative proportions of immature and mature osteoblasts control the degree of osteoclastic activity. In addition, osteoclasts control osteoblasts differentially depending on their stage of differentiation. Despite the tremendous complexity of the bone regulatory system and its fragmentary understanding, we obtain surprisingly good correlations between the model simulations and the experimental observations extracted from the literature. The model results corroborate all behaviors of the bone remodeling system that we have simulated, including the tight coupling between osteoblasts and osteoclasts, the catabolic effect induced by continuous administration of PTH, the catabolic action of RANKL, as well as its reversal by soluble antagonist OPG. The model is also able to simulate metabolic bone diseases such as estrogen deficiency, vitamin D deficiency, senescence and glucocorticoid excess. Conversely, possible routes for therapeutic interventions are tested and evaluated. Our model confirms that anti-resorptive therapies are unable to partially restore bone loss, whereas bone formation therapies yield better results. The model enables us to determine and evaluate potential therapies based on their efficacy. In particular, the model predicts that combinations of anti-resorptive and anabolic therapies provide significant benefits compared with monotherapy, especially for certain type of skeletal disease. Finally, the model clearly indicates that increasing the size of the pool of preosteoblasts is an essential ingredient for the therapeutic manipulation of bone formation. This model was conceived as the first step in a bone turnover modeling platform. These initial modeling results are extremely encouraging and lead us to proceed with additional explorations into bone turnover and skeletal remodeling.
This model corresponds to the core model published in the paper. There is no corresponding plot to reproduce for this model.
To obtain each of the 9 plots in the Figure 2 of the reference publication, there are some changes to be made to the core model.
The curation figure reproduces figure 2 of the reference publication. There is a corresponding SBML and Copasi files for each of the plot. See curation tab for more details.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 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.
2010-11-18 | BIOMD0000000278 | 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 remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.
2015-04-01 | E-GEOD-45656 | biostudies-arrayexpress
Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity.
2015-04-01 | GSE45656 | GEO
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: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: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:Bone homeostasis is regulated by hormones such as parathyroid hormone (PTH). While PTH can stimulate osteo-progenitor expansion and bone synthesis, how the PTH-signaling intensity in progenitors is controlled is unclear. Endochondral bone osteoblasts arise from perichondrium-derived osteoprogenitors and hypertrophic chondrocytes (HC). We found, via single-cell transcriptomics, HC descendent cells activate membrane-type 1 metalloproteinase 14 (MMP14) and the PTH pathway as they transition to osteoblasts in neonatal and adult mice. Unlike Mmp14 global knockouts, postnatal day 10 (p10) HC lineage-specific Mmp14 null mutants (Mmp14ΔHC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling, and consistent with the implied regulatory role, in Mmp14ΔHC mutants, PTH signaling is enhanced. We found HC-derived osteoblasts contribute ~50% of osteogenesis promoted by treatment with PTH 1-34 and this response was amplified in Mmp14ΔHC. MMP14 control of PTH signaling likely applies also to both HC- and non-HC-derived osteoblasts because their transcriptomes are highly similar. Our study identifies a novel paradigm of MMP14 activity-mediated modulation of PTH signaling in the osteoblast lineage, contributing new insights into bone metabolism with therapeutic significance for bone-wasting diseases.
2023-03-13 | GSE222203 | GEO