Abstract
Osteoporosis is a bone disease characterized by brittle bone and increased fracture incidence. With ageing societies worldwide, the disease presents a high burden on health systems. Furthermore, there are limited treatments for osteoporosis with just two anabolic pharmacological agents approved by the US Food and Drug Administration. Healthy bones are believed to be maintained via an intricate relationship between dual biochemical and mechanical (bio-mechanical) stimulations. It is widely considered that osteoporosis emerges as a result of disturbances to said relationship. The mechanotransduction process is key to this balance, and disruption of its dynamics in bone cells plays a role in osteoporosis development. Nonetheless, the exact details and mechanisms that drive and secure the health of bones are still elusive at the cellular and molecular scales. This study examined the dual modulation of mechanical stimulation and mechanotransduction activation dynamics in an osteoblast (OB). The aim was to find patterns of mechanotransduction dynamics demonstrating a significant change that can be mapped to alterations in the OB responses, specifically at the level of gene expression and osteogenic markers such as alkaline phosphatase. This was achieved using a three-dimensional hybrid multiscale computational model simulating mechanotransduction in the OB and its interaction with the extracellular matrix, combined with a numerical analytical technique. The model and the analysis method predict that within the noise of mechanotransduction, owing to modulation of the bio-mechanical stimulus and consequent gene expression, there are unique events that provide signatures for a shift in the system's dynamics. Furthermore, the study uncovered molecular interactions that can be potential drug targets.
Highlights
Osteoporosis as a skeletal disease presents a burden to health systems worldwide while the average life expectancy increases
This study presents a computational approach where a hybrid multiscale model, combining a mechanical model with the agent-based approach (Mech-Agent-based model (ABM)), was utilised to examine modulation of biomechanical signals and their influence on cellular events leading to the expression of extracellular matrix (ECM) proteins (ECMp) that modify bone material properties
This study demonstrates that dual modulation of mechanical stimuli and mechanotransduction dynamics, at the level of the Extracellular Regulated Kinase (ERK) pathway, impact modalities of ECMp mRNA expression and that the activation state of integrins may contribute to the shift of the system dynamics, that contribute to the emergence of osteoporosis[17,20,21]
Summary
Osteoporosis as a skeletal disease presents a burden to health systems worldwide while the average life expectancy increases. OB contribute to the anabolic process by depositing organic material such as collagen, alkaline phosphatase (ALP), osteopontin (OPN) and osteocalcin (OCN) in ECM, and leads to the formation of hydroxyapatite; giving bone its mechanical properties (such as strength and elasticity). They sense, integrate and respond to these stimuli to maintain the balance between catabolic and anabolic events. Disturbance of this balance leads to osteoporosis
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