Theoretical investigation of the role of the RANK–RANKL–OPG system in bone remodeling

The RANK–RANKL–OPG system is an essential signaling pathway involved in bone cell–cell communication, with ample evidence that modification of the RANK–RANKL–OPG signaling pathway has major effects on bone remodeling. The first focus of this paper is to demonstrate that a theoretical model of bone cell–cell interactions is capable of qualitatively reproducing changes in bone associated with RANK–RANKL–OPG signaling. To do this we consider either biological experiments or bone diseases related to receptor and/or ligand deficiencies, including RANKL over-expression, ablation of OPG production and/or RANK receptor modifications. The second focus is to investigate a wide range of possible therapeutic strategies for re-establishing bone homeostasis for various pathologies of the RANK–RANKL–OPG pathway. These simulations indicate that bone diseases associated with the RANK–RANKL–OPG pathway are very effective in triggering bone resorption compared to bone formation. These results align with Hofbauerʹs “convergence hypothesis”, which states that catabolic bone diseases most effectively act through the RANK–RANKL–OPG system. Additionally, we demonstrate that severity of catabolic bone diseases strongly depends on how many components of this pathway are affected. Using optimization algorithms and the theoretical model, we identify a variety of successful “virtual therapies” for different disease states using both single and dual therapies.