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BIOMD0000000279 - Komarova2005_PTHaction_OsteoclastOsteoblastCoupling

 

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Reference Publication
Publication ID: 15860557
Komarova SV.
Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone.
Endocrinology 2005 Aug; 146(8): 3589-3595
Faculty of Dentistry, McGill University, 3640 University Street, Montreal, Quebec, Canada H3A 2B2. svetlana.komarova@mcgill.ca  [more]
Model
Original Model: CellML logo
Submitter: Vijayalakshmi Chelliah
Submission ID: MODEL1011230000
Submission Date: 23 Nov 2010 14:03:27 UTC
Last Modification Date: 09 Oct 2014 16:33:55 UTC
Creation Date: 23 Nov 2010 10:56:52 UTC
Encoders:  Catherine Lloyd
   Vijayalakshmi Chelliah
   Svetlana V Komarova
set #1
bqbiol:hasProperty Human Disease Ontology glucocorticoid-remediable aldosteronism
set #2
bqbiol:occursIn Taxonomy Chordata
set #3
bqmodel:isDerivedFrom BioModels Database Komarova2003_BoneRemodeling
set #4
bqbiol:isVersionOf Gene Ontology response to parathyroid hormone
Gene Ontology regulation of bone remodeling
Notes

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.

Model
Publication ID: 15860557 Submission Date: 23 Nov 2010 14:03:27 UTC Last Modification Date: 09 Oct 2014 16:33:55 UTC Creation Date: 23 Nov 2010 10:56:52 UTC
Mathematical expressions
Rules
Rate Rule (variable: Osteoclasts) Rate Rule (variable: Osteoblasts) Rate Rule (variable: BoneMass) Assignment Rule (variable: y1)
Assignment Rule (variable: y2) Assignment Rule (variable: x1_bar) Assignment Rule (variable: x2_bar) Assignment Rule (variable: gamma)
Physical entities
Compartments Species
Compartment Osteoclasts Osteoblasts BoneMass
Global parameters
y1 y2 x1_bar x2_bar
alpha1 beta1 alpha2 beta2
k1 k2 g11 g21
g12 g22 gamma  
Reactions (0)
Rules (8)
 
 Rate Rule (name: x1) d [ Osteoclasts] / d t= alpha1*x1^g11*x2^g21-beta1*x1
 
 Rate Rule (name: x2) d [ Osteoblasts] / d t= alpha2*x1^g12*x2^g22-beta2*x2
 
 Rate Rule (name: z) d [ BoneMass] / d t= k2*y2-k1*y1
 
 Assignment Rule (name: y1) y1 = piecewise(x1-x1_bar, x1 > x1_bar, 0)
 
 Assignment Rule (name: y2) y2 = piecewise(x2-x2_bar, x2 > x2_bar, 0)
 
 Assignment Rule (name: x1_bar) x1_bar = (beta1/alpha1)^((1-g22)/gamma)*(beta2/alpha2)^(g21/gamma)
 
 Assignment Rule (name: x2_bar) x2_bar = (beta1/alpha1)^(g12/gamma)*(beta2/alpha2)^((1-g11)/gamma)
 
 Assignment Rule (name: gamma) gamma = g12*g21-(1-g11)*(1-g22)
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 Osteoclasts
Compartment: Compartment
Initial concentration: 1.06066
 
 Osteoblasts
Compartment: Compartment
Initial concentration: 212.132
 
 BoneMass
Compartment: Compartment
Initial concentration: 100.0
 
Global Parameters (15)
 
   y1
Value: NaN
 
   y2
Value: NaN
 
   x1_bar
Value: NaN
 
   x2_bar
Value: NaN
 
 alpha1
Value: 3.0
Constant
 
 beta1
Value: 0.2
Constant
 
 alpha2
Value: 4.0
Constant
 
 beta2
Value: 0.02
Constant
 
 k1
Value: 0.24
Constant
 
 k2
Value: 0.0017
Constant
 
 g11
Value: 0.5
Constant
 
 g21
Value: -0.5
Constant
 
 g12
Value: 1.0
Constant
 
 g22
Constant
 
  gamma
Value: NaN
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000279

Curator's comment: (updated: 23 Nov 2010 14:19:18 GMT)

The model reproduces Figures 1B and 2A of the reference publication. 1) The panel (A) of the curation figure corresponds to Figure 1B of the publication. These plots shows the simulation of Osteoclasts (x1), Osteoblasts (x2) and Bone Mass (z%) upon stimulation by PTH with varying g21. Increase in g21 from -0.5 to -0.1 (green), 0.1 (blue) and 0.3 (red) as a 1-day burst.

2) The panel (B) of the curation figure corresponds to Figure 2A of the publication. The changes in bone mass are observed by an increase in g21 for 1-day from -0.5 to 0 (green), 0.1 (blue) and 0.15 (red). The plots are made for three sets of g12 and k2 values.

The model was integrated and simulated using Copasi v4.6 (Build 32). Copasi files corresponding to each of the plots in the curation figure would be available for download.

Additional file(s)
  • Komarova (2005) - Panel A.:
    Komarova (2005): Simulation of Osteoclasts, Osteoblasts and Bone Mass upon stimulation by PTH with an increase in g21 from -0.5 to -0.1, 0.1 and 0.3 as a 1-d burst. [refer Figure 1B of the reference publication].
    * Panel A: g21 = -0.1 (green). [figA_green.cps]
    * Panel A: g21 = 0.1 (blue). [figA_blue.cps]
    * Panel A: g21 = 0.3 (red). [figA_red.cps]
  • Komarova (2005) - Panel B.:
    Komarova (2005): The changes in bone mass as observed by an increase in g21 from -0.5 to 0, 0.1 and 0.15 for 1-day, with 3 sets of g12 and k2 values. [refer Figure 2A of the reference publication].
    * Panel B1: g12 = 0.5; k2 = 0.005; g21 = 0.0 (green). [figB1_green.cps]
    * Panel B1: g12 = 0.5; k2 = 0.005; g21 = 0.1 (blue). [figB1_blue.cps]
    * Panel B1: g12 = 0.5; k2 = 0.005; g21 = 0.15 (red). [figB1_red.cps]

    * Panel B2: g12 = 0.98; k2 = 0.0017; g21 = 0.0 (green). [figB2_green.cps]
    * Panel B2: g12 = 0.98; k2 = 0.0017; g21 = 0.1 (blue). [figB2_blue.cps]
    * Panel B2: g12 = 0.98; k2 = 0.0017; g21 = 0.15 (red). [figB2_red.cps]

    * Panel B3: g12 = 1.4; k2 = 0.00075; g21 = 0.0 (green). [figB3_green.cps]
    * Panel B3: g12 = 1.4; k2 = 0.00075; g21 = 0.1 (blue). [figB3_blue.cps]
    * Panel B3: g12 = 1.4; k2 = 0.00075; g21 = 0.15 (red). [figB3_red.cps]
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