title: In silico modeling and simulation of bone biology: a proposal.
abstract: Contemporary, computer-based mathematical modeling techniques make it possible to represent complex biological mechanisms in a manner that permits hypothesis testing in silico. This perspective shows how such approaches might be applied to bone remodeling and therapeutic research. Currently, the dominant conceptual model applied in bone research involves the dynamic balance between the continual build-up and breakdown of bone matrix by two cell types, the osteoblasts and osteoclasts, acting together as a coordinated, remodeling unit. This conceptualization has served extraordinarily well as a focal point for understanding how mutations, chemical mediators, and mechanical force, as well as external influences (e.g., drugs, diet) affect bone structure and function. However, the need remains to better understand and predict the consequences of manipulating any single factor, or combination of factors, within the context of this complex system's multiple interacting pathways. Mathematical models are a natural extension of conceptual models, providing dynamic, quantitative descriptions of the relationships among interacting components. This formalization creates the ability to simulate the natural behavior of a system, as well as its modulation by therapeutic or dietetic interventions. A number of mathematical models have been developed to study complex bone functions, but most include only a limited set of biological components needed to address a few specific questions. However, it is possible to develop larger, multiscale models that capture the dynamic interactions of many biological components and relate them to important physiological or pathological outcomes that allow broader study. Examples of such models include entelos' physiolab platforms. These models simulate the dynamic, quantitative interactions among a biological system's biochemicals, cells, tissues, and organs and how they give rise to key physiologic and pathophysiologic outcomes. We propose that a similar predictive, dynamical, multiscale mathematical model of bone remodeling and metabolism would provide a better understanding of the mechanisms governing these phenomena as well as serve as an in silico platform for testing pharmaceutical and clinical interventions on metabolic bone disease.
authors.affiliation: In Silico R&D Department, Entelos, Inc., Foster City, California, USA.
authors.forename: Nadine A
authors.initials: NA
authors.lastname: Defranoux
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Stokes
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Young
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Kahn
mesh_terms: D001847:Bone Diseases / Q000188:drug therapy* / Q000378:metabolism*; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism / Q000503:physiopathology; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological