In silico experiments of bone remodeling explore metabolic diseases and their drug treatment

Abstract

Bone structure and function are maintained by well-regulated bone metabolism and remodeling. Although the underlying molecular and cellular mechanisms are now being understood, physiological and pathological states of bone are still difficult to predict due to the complexity of intercellular signaling. We have now developed a novel in silico experimental platform, V-Bone, to integratively explore bone remodeling by linking complex microscopic molecular/cellular interactions to macroscopic tissue/organ adaptations. Mechano-biochemical couplings modeled in V-Bone relate bone adaptation to mechanical loading and reproduce metabolic bone diseases such as osteoporosis and osteopetrosis. V-Bone also enables in silico perturbation on a specific signaling molecule to observe bone metabolic dynamics over time. We also demonstrate that this platform provides a powerful way to predict in silico therapeutic effects of drugs against metabolic bone diseases. We anticipate that these in silico experiments will substantially accelerate research into bone metabolism and remodeling.

In silico tools predict effects of drugs on bone remodelling

“…The metabolic process of bone remodelling is crucial for the maintenance of healthy skeletal homeostasis and for skeletal adaptations to imposed mechanical or biological changes 1,2 . Bone remodelling is carried out by the so-called bone multicellular units (BMUs), composed of osteoclasts resorbing the old or damaged bone and osteoblasts depositing new bone.…”

“…1). In a new study, Kameo et al 2 have developed an in silico experimental platform for capturing the complexities of bone remodelling and adaptation, which could accelerate research in this area and lead to novel therapies.…”

“…The model described in Kameo et al 2 is an extension of the authors' previous mechanics-driven modelling work and now explicitly incorporates the process of osteocytes producing biochemical signals in response to a mechanical stimulus. These biochemical signals activate osteoclasts and osteoblasts through complex signalling cascades, including pathways that are dysregu lated in many biochemical bone metabolic diseases.…”

“…To validate the model, the researchers tested the ability of the model to capture adaptation to mechani cal loading, at the level of single trabeculae and a cube of cancellous bone (0.4 mm³). Subsequently, Kameo et al 2 successfully simulated, both quantitatively and qualitatively, the experimentally observed development and progression of osteoporosis and osteopetrosis on a whole femur as induced by unloading or by abnormal expression of RANK ligand (RANKL).…”

“…After the initial qualitative checks, the model platform was quantitatively validated by simulating in vivo experiments of mice deficient in semaphorin 3A (Sema3A; a signalling molecule that inhibits osteoclastic bone resorption and promotes osteoblastic bone formation) and mice treated with Sema3A. Kameo et al 2 compared the simulated results with results from the corresponding in vivo experiments, including structural parameters such as the bone volume over total volume and the total number of trabeculae and biological read-outs such as the spatial distribution of signalling molecules, osteoclasts and osteoblasts. Kameo et al 2 sought to demonstrate the added value of their modelling platform in exploring and explaining the progress of osteoporosis and the effect of four the mechanical mechanisms of bone remodelling date back to the nineteenth century when Julius Wolff introduced his law ('Wolff 's law'), stating that bone will adapt to the loads under which it is placed 3 .…”