Dataset Information

Komarova2005_PTHaction_OsteoclastOsteoblastCoupling

ABSTRACT: 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.

DISEASE(S): Glucocorticoid-remediable Aldosteronism

SUBMITTER: Vijayalakshmi Chelliah

PROVIDER: BIOMD0000000279 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000279?filename=BIOMD0000000279-biopax2.owl	Owl
	BIOMD0000000279?filename=BIOMD0000000279-biopax3.owl	Owl
	BIOMD0000000279?filename=BIOMD0000000279-matlab.m	Other
	BIOMD0000000279?filename=BIOMD0000000279-octave.m	Other
	BIOMD0000000279?filename=BIOMD0000000279.m	Other

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Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone.

Komarova Svetlana V SV

Endocrinology 20050428 8

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 ...[more]

PMID: 15860557

Similar Datasets

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.

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.