Gene regulatory network analysis identifies MYL1, MDH2, GLS, and TRIM28 as the principal proteins in the response of mesenchymal stem cells to Mg2+ ions.

Magnesium (Mg)-based implants have emerged as a promising alternative for orthopedic applications, owing to their bioactive properties and biodegradability. As the implants degrade, Mg2+ ions are released, influencing all surrounding cell types, especially mesenchymal stem cells (MSCs). MSCs are vital for bone tissue regeneration, therefore, it is essential to understand their molecular response to Mg2+ ions in order to maximize the potential of Mg-based biomaterials. In this study, we conducted a gene regulatory network (GRN) analysis to examine the molecular responses of MSCs to Mg2+ ions. We used time-series proteomics data collected at 11 time points across a 21-day period for the GRN construction. We studied the impact of Mg2+ ions on the resulting networks and identified the key proteins and protein interactions affected by the application of Mg2+ ions. Our analysis highlights MYL1, MDH2, GLS, and TRIM28 as the primary targets of Mg2+ ions in the response of MSCs during 1-21 days phase. Our results also identify MDH2-MYL1, MDH2-RPS26, TRIM28-AK1, TRIM28-SOD2, and GLS-AK1 as the critical protein relationships affected by Mg2+ ions. By offering a comprehensive understanding of the regulatory role of Mg2+ ions on MSCs, our study contributes valuable insights into the molecular response of MSCs to Mg-based materials, thereby facilitating the development of innovative therapeutic strategies for orthopedic applications.

The osteogenetic activities of mesenchymal stem cells in response to Mg2+ ions and inflammatory cytokines: a numerical approach using fuzzy logic controllers.

Magnesium (Mg2+) ions are frequently reported to regulate osteogenic activities of mesenchymal stem cells (MSCs). In this study, we propose a numerical model to study the regulatory importance of Mg2+ ions on MSCs osteoblastic differentiation in the presence of an inflammatory response. A fuzzy logic controller was formulated to receive the concentrations of Mg2+ ions and the inflammatory cytokines of TNF-α, IL-10, IL-1ß, and IL-8 as cellular inputs and predict the cells' early and late differentiation rates. Five sets of empirical data obtained from published cell culture experiments were used to calibrate the model. The model successfully reproduced the empirical data regarding the concentration- and phase-dependent effect of Mg2+ ions on the differentiation process. In agreement with the experiments, the model showed the stimulatory role of Mg2+ ions on the early differentiation phase, once administered at low concentration, and their inhibitory role on the late differentiation phase. The numerical approach used in this study suggested 6-8 mM as the most effective concentration of Mg2+ ions in promoting the early differentiation process. Also, the proposed model sheds light on the fundamental differences in the behavioral properties of cells cultured in different experiments, e.g. differentiation rate and the sensitivity of the cultured cells to stimulatory signals such as Mg2+ ions. Thus, it can be used to interpret and compare different empirical findings. Moreover, the model successfully reproduced the nonlinearities in the concentration-dependent role of the inflammatory cytokines in early and late differentiation rates. Overall, the proposed model can be employed in studying the osteogenic properties of Mg-based implants in the presence of an inflammatory response.

Magnesium ions regulate mesenchymal stem cells population and osteogenic differentiation: A fuzzy agent-based modeling approach.

Mesenchymal stem cells (MSCs) are proliferative and multipotent cells that play a key role in the bone regeneration process. Empirical data have repeatedly shown the bioregulatory importance of magnesium (Mg) ions in MSC growth and osteogenesis. In this study, we propose an agent-based model to predict the spatiotemporal dynamics of the MSC population and osteogenic differentiation in response to Mg2+ ions. A fuzzy-logic controller was designed to govern the decision-making process of cells by predicting four cellular processes of proliferation, differentiation, migration, and mortality in response to several important bioregulatory factors such as Mg2+ ions, pH, BMP2, and TGF-ß1. The model was calibrated using the empirical data obtained from three sets of cell culture experiments. The model successfully reproduced the empirical observations regarding live cell count, viability, DNA content, and the differentiation-related markers of alkaline phosphate (ALP) and osteocalcin (OC). The simulation results, in agreement with the empirical data, showed that Mg2+ ions within 3-6 mM concentration have the highest stimulation effect on cell population growth. The model also correctly reproduced the stimulatory effect of Mg2+ ions on ALP and its inhibitory effect on OC as the early and late differentiation markers, respectively. Besides, the numerical simulation shed light on the innate cellular differences of the cells cultured in different experiments in terms of the proliferative capacity as well as sensitivity to Mg2+ ions. The proposed model can be adopted in the study of the osteogenesis around Mg-based implants where ions released due to degradation interact with local cells and regulate bone regeneration.

Biomechanical evaluation of intramedullary nail and bone plate for the fixation of distal metaphyseal fractures.

Surgical treatment of distal metaphyseal fractures remains problematic, and whilst both intramedullary nailing and bone plate fixation are known as the acceptable methods for the internal fixation of this kind of fractures, neither technique demonstrated satisfactory clinical outcomes. In this research, a finite element based investigation was made to compare these two fixation techniques for the fixation of distal tibia fractures from the biomechanics point of view. For this purpose, a 3mm transverse fracture gap was created at the distal metaphyseal region of tibia and fixed by use of either a nail or a plate. The von Mises stress, interfragmentary movements, and the production of different tissue phenotypes at the fracture site were calculated. Results of this study showed that plating offers more advantageous biomechanical conditions at the fracture site, in which it provides sufficient amount of axial interfragmentary movement and considerable amount of cartilage production, while intramedullary nailing restricts axial movements but causes high magnitude of shear movements. However, nailing is superior to plating from the mechanical point of view and provides earlier weight bearing. In addition, it was shown that by using composite materials, biomechanical behavior of both fixation techniques will be improved through decreasing risk of failure and promoting cartilaginous tissue production.