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BIOMD0000000278 - Lemaire2004 - Role of RANK/RANKL/OPG pathway in bone remodelling process

 

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Reference Publication
Publication ID: 15234198
Lemaire V, Tobin FL, Greller LD, Cho CR, Suva LJ.
Modeling the interactions between osteoblast and osteoclast activities in bone remodeling.
J. Theor. Biol. 2004 Aug; 229(3): 293-309
Scientific Computing and Mathematical Modeling, GlaxoSmithKline, King of Prussia, PA, USA. lemaire@cnd.mcgill.ca  [more]
Model
Original Model: BIOMD0000000278.origin
Submitter: Camille Laibe
Submission ID: MODEL1006230067
Submission Date: 23 Jun 2010 09:12:22 UTC
Last Modification Date: 09 Oct 2014 16:31:19 UTC
Creation Date: 18 Nov 2010 11:20:34 UTC
Encoders:  Vijayalakshmi Chelliah
   Vincent Lemaire
   Frank L Tobin
set #1
bqbiol:hasProperty Human Disease Ontology glucocorticoid-remediable aldosteronism
set #2
bqbiol:hasTaxon Taxonomy Chordata
set #3
bqbiol:isVersionOf Gene Ontology regulation of bone remodeling
Notes

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.

Model
Publication ID: 15234198 Submission Date: 23 Jun 2010 09:12:22 UTC Last Modification Date: 09 Oct 2014 16:31:19 UTC Creation Date: 18 Nov 2010 11:20:34 UTC
Mathematical expressions
Rules
Assignment Rule (variable: D_B) Assignment Rule (variable: Phi_C) Assignment Rule (variable: Phi_L) Assignment Rule (variable: Phi_P)
Assignment Rule (variable: Pbar) Assignment Rule (variable: P_O) Assignment Rule (variable: P_S) Rate Rule (variable: Responding_Osteoblasts)
Rate Rule (variable: Active_Osteoblasts) Rate Rule (variable: Active_Osteoclasts)    
Physical entities
Compartments Species
Compartment Responding_Osteoblasts Active_Osteoblasts Active_Osteoclasts
Global parameters
C_s D_A d_B D_C
D_R f0 I_L I_O
I_P K k1 k2
k3 k4 k5 k6
k_B K_L_P kO K_O_P
k_P r_L S_P Phi_C
D_B Phi_L Phi_P Pbar
P_O P_S    
Reactions (0)
Rules (10)
 
 Assignment Rule (name: D_B) D_B = f0*d_B
 
 Assignment Rule (name: Phi_C) Phi_C = (C+f0*C_s)/(C+C_s)
 
 Assignment Rule (name: Phi_L) Phi_L = k3/k4*K_L_P*Phi_P*B/(1+k3*K/k4+k1/(k2*kO)*(I_O+K_O_P*R/Phi_P))*(1+I_L/r_L)
 
 Assignment Rule (name: Phi_P) Phi_P = (Pbar+P_O)/(Pbar+P_S)
 
 Assignment Rule (name: Pbar) Pbar = I_P/k_P
 
 Assignment Rule (name: P_O) P_O = S_P/k_P
 
 Assignment Rule (name: P_S) P_S = k6/k5
 
 Rate Rule (name: R) d [ Responding_Osteoblasts] / d t= D_R*Phi_C-D_B*R/Phi_C
 
 Rate Rule (name: B) d [ Active_Osteoblasts] / d t= D_B*R/Phi_C-k_B*B
 
 Rate Rule (name: C) d [ Active_Osteoclasts] / d t= D_C*Phi_L-D_A*Phi_C*C
 
 Compartment Spatial dimensions: 3.0  Compartment size: 1.0
 
 Responding_Osteoblasts
Compartment: Compartment
Initial concentration: 7.734E-4
 
 Active_Osteoblasts
Compartment: Compartment
Initial concentration: 7.282E-4
 
 Active_Osteoclasts
Compartment: Compartment
Initial concentration: 9.127E-4
 
Global Parameters (30)
 
 C_s
Value: 0.005
Constant
 
 D_A
Value: 0.7
Constant
 
 d_B
Value: 0.7
Constant
 
 D_C
Value: 0.0021
Constant
 
 D_R
Value: 7.0E-4
Constant
 
 f0
Value: 0.05
Constant
 
 I_L
Constant
 
 I_O
Constant
 
 I_P
Constant
 
 K
Value: 10.0
Constant
 
 k1
Value: 0.01
Constant
 
 k2
Value: 10.0
Constant
 
 k3
Value: 5.8E-4
Constant
 
 k4
Value: 0.017
Constant
 
 k5
Value: 0.02
Constant
 
 k6
Value: 3.0
Constant
 
 k_B
Value: 0.189
Constant
 
 K_L_P
Value: 3000000.0
Constant
 
 kO
Value: 0.35
Constant
 
 K_O_P
Value: 200000.0
Constant
 
 k_P
Value: 86.0
Constant
 
 r_L
Value: 1000.0
Constant
 
 S_P
Value: 250.0
Constant
 
   Phi_C
Value: NaN
 
   D_B
Value: NaN
 
   Phi_L
Value: NaN
 
   Phi_P
Value: NaN
 
   Pbar
Value: NaN
 
   P_O
Value: NaN
 
   P_S
Value: NaN
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000278

Curator's comment: (updated: 22 Nov 2010 17:19:57 GMT)

The model corresponds to the core model published in the paper. There is no corresponding plot to be reproduced for this model.However, fig2 of the reference publication has been reproduced which was obtained by extending the core model. Each of the 9 plots in the Figure 2 of the reference publication are reproduced as curation figure here. Each plot has its corresponding model file (SBML file) and simulation file (Copasi file) which would be available to download. Each of these SBML files have notes on how and what extension has been made.

The model was integrated and curated using Copasi v4.6 (Build 32).

Additional file(s)
  • Lemaire (2004) - remove C:
    This model is an extension of the core model in which Osteoclasts (C) are being removed constantly from day 20 to day 80 (i.e. for 60 days) at 0.00029pM/day. The model reproduces (Figure 5 of the curation figure), the middle plot of Figure 2B of the reference publication.
  • Lemaire (2004) - add C:
    This model is an extension of the core model in which Osteoclasts (C) are being added constantly from day 20 to day 80 (i.e. for 60 days) at 0.0001pM/day. The model reproduces (Figure 2 of the curation figure), the middle plot of Figure 2A of the reference publication.
  • Lemaire (2004) - remove B:
    This model is an extension of the core model in which, Osteoblasts (B) are being removed constantly from day 20 to day 80 (i.e. for 60 days) at 8.3e-005pM/day. The model reproduces (Figure 4 of the curation figure), the first plot of Figure 2B of the reference publication.
  • Lemaire (2004) - add OPG:
    This model is an extension of the core model in which, the Osteoprotegerin-OPGs (I_O) are being added constantly from day 20 to day 80 (i.e. for 60 days) at 200000pM/day. The model reproduces (Figure 8 of the curation figure), the middle plot of Figure 2C of the reference publication.
  • Lemaire (2004) - add R:
    This model is an extension of the core model in which the Responding Osteoblasts (R) are being added constantly from day 20 to day 80 (i.e. for 60 days) at 0.0001pM/day. The model reproduces (Figure 3 of the curation figure), the last plot of Figure 2A of the reference publication.
  • Lemaire (2004) - add B:
    This model is an extension of the core model in which Osteoblasts (B) are being added constantly from day 20 to day 80 (i.e. for 60 days) at 0.0001pM/day. The model reproduces (Figure 1 of the curation figure), the first plot of Figure 2A of the reference publication.
  • Lemaire (2004) - add OPG and RANKL:
    This model is an extension of the core model in which, RANKLs (I_L) are being added constantly from day 20 at 10000pM/day and Osteoprotegerin-OPGs (I_O) being added constantly 60 days later (i.e. at day 80) at 90000pM/day. The model reproduces (Figure 9 of the curation figure), the last plot of Figure 2C of the reference publication.
  • Lemaire (2004) - add PTH:
    This model is an extension of the core model in which, PTHs (I_P) are being added constantly from day 20 to day 80 (i.e. for 60 days) at 1000pM/day. The model reproduces (Figure 7 of the curation figure), the first plot of Figure 2C of the reference publication.
  • Lemaire (2004) - remove R:
    This model is an extension of the core model in which the Responding Osteoblasts (R) are being removed constantly from day 20 to day 80 (i.e. for 60 days) at 0.00012pM/day. The model reproduces (Figure 6 of the curation figure), the last plot of Figure 2B of the reference publication.
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