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Issue No.05 - Sept.-Oct. (2012 vol.9)
pp: 1366-1378
Nicola Paoletti , Sch. of Sci. & Technol., Univ. of Camerino, Camerino, Italy
Pietro Lio , Comput. Lab., Univ. of Cambridge, Cambridge, UK
Emanuela Merelli , Sch. of Sci. & Technol., Univ. of Camerino, Camerino, Italy
Marco Viceconti , Dept. of Mech. Eng., Univ. of Sheffield, Sheffield, UK
Our work focuses on bone remodeling with a multiscale breadth that ranges from modeling intracellular and intercellular RANK/RANKL signaling to tissue dynamics, by developing a multilevel modeling framework. Several important findings provide clear evidences of the multiscale properties of bone formation and of the links between RANK/RANKL and bone density in healthy and disease conditions. Recent studies indicate that the circulating levels of OPG and RANKL are inversely related to bone turnover and Bone Mineral Density (BMD) and contribute to the development of osteoporosis in postmenopausal women, and thalassemic patients. We make use of a spatial process algebra, the Shape Calculus, to control stochastic cell agents that are continuously remodeling the bone. We found that our description is effective for such a multiscale, multilevel process and that RANKL signaling small dynamic concentration defects are greatly amplified by the continuous alternation of absorption and formation resulting in large structural bone defects. This work contributes to the computational modeling of complex systems with a multilevel approach connecting formal languages and agent-based simulation tools.
tissue engineering, bone, calculus, cellular biophysics, diseases, formal languages, medical computing, process algebra, stochastic systems, formal languages, multilevel computational modeling, quantitative analysis, bone remodeling, multiscale breadth, intracellular RANK-RANKL signaling, intercellular RANK-RANKL signaling, tissue dynamics, disease, bone mineral density, osteoporosis, postmenopausal women, thalassemic patients, spatial process algebra, Shape Calculus, stochastic cell agents, dynamic concentration defects, structural bone defects, agent-based simulation tools, Bones, Shape, Three dimensional displays, Calculus, Computational modeling, Biological system modeling, Osteoporosis, agent-based simulation., Osteoporosis, multilevel, shape calculus, bone remodeling, multiscale, RANK/RANKL
Nicola Paoletti, Pietro Lio, Emanuela Merelli, Marco Viceconti, "Multilevel Computational Modeling and Quantitative Analysis of Bone Remodeling", IEEE/ACM Transactions on Computational Biology and Bioinformatics, vol.9, no. 5, pp. 1366-1378, Sept.-Oct. 2012, doi:10.1109/TCBB.2012.51
[1] S. Jabbar, J. Drury, J. Fordham, H. Datta, R. Francis, and S. Tuck, "Osteoprotegerin, RANKL and Bone Turnover in Postmenopausal Osteoporosis," J. Clinical Pathology, vol. 64, no. 4, pp. 354-357, 2011.
[2] N.e.a. Morabito, "Osteoprotegerin and RANKL in the Pathogenesis of Thalassemia-Induced Osteoporosis: New Pieces of the Puzzle," J. Bone and Mineral Research, vol. 19, no. 5, pp. 722-727, 2004.
[3] P. Liò, E. Merelli, N. Paoletti, and M. Viceconti, "A Combined Process Algebraic and Stochastic Approach to Bone Remodeling," Electronic Notes in Theoretical Computer Science, vol. 277, pp. 41-52, 2011.
[4] N. Paoletti, P. Liò, E. Merelli, and M. Viceconti, "Osteoporosis: A Multiscale Modeling Viewpoint," Proc. Ninth Int'l Conf. Computational Methods in Systems Biology, pp. 183-193, 2011.
[5] E. Bartocci, D. Cacciagrano, M.Di Berardini, E. Merelli, and L. Tesei, "Timed Operational Semantics and Well-Formedness of Shape Calculus," Scientific Annals of Computer Science, vol. 20, pp. 32-52, 2010.
[6] E. Bartocci, F. Corradini, M.Di Berardini, E. Merelli, and L. Tesei, "Shape Calculus. A Spatial Mobile Calculus for 3D Shapes," Scientific Annals of Computer Science, vol. 20, pp. 1-31, 2010.
[7] L. Milanesi, P. Romano, G. Castellani, D. Remondini, and P. Liò, "Trends in Modeling Biomedical Complex Systems," BMC Bioinformatics, vol. 10, no. Suppl 12, 2009.
[8] L. Geris, J. Vander Sloten, and H. Van Oosterwyck, "In Silico Biology of Bone Modelling and Remodelling: Regeneration," Philosophical Trans. Royal Soc. A: Math., Physical and Eng. Sciences, vol. 367, no. 1895, pp. 2031-2053, 2009.
[9] F. Gerhard, D. Webster, G. van Lenthe, and R. Müller, "In Silico Biology of Bone Modelling and Remodelling: Adaptation," Philosophical Trans. Royal Soc. A: Math., Physical and Eng. Sciences, vol. 367, no. 1895, pp. 2011-2030, 2009.
[10] P. Pivonka and S. Komarova, "Mathematical Modeling in Bone Biology: From Intracellular Signaling to Tissue Mechanics," Bone, vol. 47, no. 2, pp. 181-189, 2010.
[11] M. Viceconti, L. Bellingeri, L. Cristofolini, and A. Toni, "A Comparative Study on Different Methods of Automatic Mesh Generation of Human Femurs," Medical Eng. and Physics, vol. 20, no. 1, pp. 1-10, 1998.
[12] J. Fisher and T. Henzinger, "Executable Cell Biology," Nature Biotechnology, vol. 25, no. 11, pp. 1239-1249, 2007.
[13] A. Tovar, "Bone Remodeling as a Hybrid Cellular Automaton Optimization Process," PhD dissertation, Univ. of Notre Dame, 2004.
[14] L. Li and H. Yokota, "Application of Petri Nets in Bone Remodeling," Gene Regulation and Systems Biology, vol. 3, pp. 105-114, 2009.
[15] D. Cacciagrano, F. Corradini, E. Merelli, and L. Tesei, "Multiscale Bone Remodelling with Spatial P Systems," Proc. Fourth Workshop Membrane Computing and Biologically Inspired Process Calculi, 2010.
[16] P. Liò, E. Merelli, and N. Paoletti, "Multiple Verification in Computational Modeling of Bone Pathologies," Proc. CompMod, pp. 82-96, 2011.
[17] A.T. Bittig and A.M. Uhrmacher, "Spatial Modeling in Cell Biology at Multiple Levels," Proc. Winter Simulation Conf., pp. 608-619, 2010.
[18] F. Ciocchetta and M.L. Guerriero, "Modelling Biological Compartments in Bio-PEPA," Electronic Notes Theoretical Computer Science, vol. 227, pp. 77-95, Jan. 2009.
[19] A. Regev, E.M. Panina, W. Silverman, L. Cardelli, and E. Shapiro, "BioAmbients: An Abstraction for Biological Compartments," Theoretical Computer Science, vol. 325, no. 1, pp. 141-167, 2004.
[20] C. Priami and P. Quaglia, "Beta Binders for Biological Interactions," Computational Methods in Systems Biology, vol. 3082, pp. 20-33, 2005.
[21] L. Cardelli and P. Gardner, "Processes in Space," Programs, Proofs, Processes, vol. 6158, pp. 78-87, 2010.
[22] M. John, C. Lhoussaine, J. Niehren, and A. Uhrmacher, "The Attributed $\pi$ -Calculus with Priorities," Trans. Computational Systems Biology XII, vol. 5945, pp. 13-76, 2010.
[23] A. Stefanek, M. Vigliotti, and J.T. Bradley, "Spatial Extension of Stochastic $\pi$ Calculus," Proc. Eighth Workshop Process Algebra and Stochastically Timed Activities, pp. 109-117, Aug. 2009.
[24] R. Milner, A Calculus of Communicating Systems, vol. 92, Springer-Verlag, 1980.
[25] D. Epari, G. Duda, and M. Thompson, "Mechanobiology of Bone Healing and Regeneration: In Vivo Models," Proc. Institution of Mechanical Engineers, Part H, J. Eng. in Medicine, vol. 224, no. 12, pp. 1533-1541, 2010.
[26] S. Komarova, R. Smith, S. Dixon, S. Sims, and L. Wahl, "Mathematical Model Predicts a Critical Role for Osteoclast Autocrine Regulation in the Control of Bone Remodeling," Bone, vol. 33, no. 2, pp. 206-215, 2003.
[27] M. Ryser, N. Nigam, and S. Komarova, "Mathematical Modeling of Spatio-Temporal Dynamics of a Single Bone Multicellular Unit," J. Bone and Mineral Research, vol. 24, no. 5, pp. 860-870, 2009.
[28] J. Hillston, A Compositional Approach to Performance Modelling, no. 12, Cambridge Univ. Press, 1996.
[29] M. North, T. Howe, N. Collier, and J. Vos, "A Declarative Model Assembly Infrastructure for Verification and Validation," Advancing Social Simulation: The First World Congress, pp. 129-140, Springer, 2007.
[30] X. Yang and Y. Young, "Cellular Automata, PDEs, and Pattern Formation," Handbook of Bioinspired Algorithms and Applications. Chapman & Hall/CRC Computer and Information Science, 2005.
[31] A. Edelstein and N. Agmon, "Brownian Simulation of Many-Particle Binding to a Reversible Receptor Array," J. Computational Physics, vol. 132, no. 2, pp. 260-275, 1997.
[32] A. Looker, H. Wahner, W. Dunn, M. Calvo, T. Harris, S. Heyse, C. Johnston Jr, and R. Lindsay, "Updated Data on Proximal Femur Bone Mineral Levels of Us Adults," Osteoporosis Int'l, vol. 8, no. 5, pp. 468-490, 1998.
[33] "T and Z Scores," , 2011.
[34] WHO Study Group on Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis "Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis," Technical Report 843, 1994.
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