Revealing hidden information in osteoblast’s mechanotransduction through analysis of time patterns of critical events

Abstract

Background: Mechanotransduction in bone cells plays a pivotal role in osteoblast differentiation and bone remodelling. Mechanotransduction provides the link between modulation of the extracellular matrix and intracellular actions. By controlling the balance between the intracellular and extracellular domains, the mechanotransduction process determines optimal functionality of the skeletal dynamics, and it is one of the possible causes of osteophatological diseases. Results: Mechanotransduction in a single osteoblast under external mechanical perturbations has been modelled in the agent based framework to reproduce the dynamics of the stochastic reaction diffusion process among molecules in the cytoplasm, nuclear and extracellular domains. The amount of molecules and fluctuations of each molecular class has been analysed in terms of recurrences of critical events. A numerical approach has been developed to invert subordination processes and to extract the directing processes from the molecular signals in order to derive the distribution of recurrence of events. Conclusions:We observed large fluctuations enclose information hidden in the noise which is beyond the dynamic variations of molecular baselines. Studying the system under different parametric conditions and stimuli, the results have shown that the waiting time distributions of each molecule are a signature of the system's dynamics. The behaviours of the molecular waiting times change with the changing of parameters presenting the same variation of patterns for similar interacting molecules and identifying specific alterations for key molecules in the mechanotransduction pathway.

Analysis of mechanotransduction dynamics during combined mechanical stimulation and modulation of the extracellular-regulated kinase cascade uncovers hidden information within the signalling noise

“…The results presented here illustrate that the ensuing gene expression events of bio-mechanical signals, in contrast with cytoplasmic mechanotransduction events [8,35], are noisier. These chaotic events were particularly evident at the level of transcribed ECMp mRNAs (e.g.…”

“…royalsocietypublishing.org/journal/rsfs Interface Focus 11: 20190136 cytoplasmic mechanotransduction events [8,35], are noisier. These chaotic events were particularly evident at the level of transcribed ECMp mRNAs (e.g.…”

“…How dual bio-mechanical stimuli achieve this is poorly understood. Nonetheless, we previously demonstrated that fluctuations in the system (OBs' mechanotransduction) are beyond mere system randomness [35], and that, with dual alteration of the mechanical load and ERK's feedback loops (i.e. ACSs), the WTDs can reflect molecular signatures of the system with respect to cytoplasmic events.…”

Dynamic Self-Reinforcement of Gene Expression Determines Acquisition and Retention of Cellular Mechanical Memory

“…Bistability alone does not contain any information about dynamics of memory development or retention, only that it can occur (24,25). Several mechanistic models have been put forward to explain the relationship between mechanics and cell differentiation (5,(26)(27)(28), but these models do not simultaneously capture 1) the timescale disparity between mechanical signaling / cell adaptation and memory development and 2) the continuous range of memory outcomes. More generally, regulatory gene network models with different topologies can give rise to memory using network motifs such as positive and negative reinforcement (29)(30)(31)(32)(33)(34).…”