Abstract
Inflammatory cytokines are key drivers of cartilage degradation in post-traumatic osteoarthritis. Cartilage degradation mediated by these inflammatory cytokines has been extensively investigated using in vitro experimental systems. Based on one such study, we have developed a computational model to quantitatively assess the impact of charged small molecules intended to inhibit IL-1 mediated cartilage degradation. We primarily focus on the simplest possible computational model of small molecular interaction with the IL-1 system—direct binding of the small molecule to the active site on the IL-1 molecule itself. We first use the model to explore the uptake and release kinetics of the small molecule inhibitor by cartilage tissue. Our results show that negatively charged small molecules are excluded from the negatively charged cartilage tissue and have uptake kinetics in the order of hours. In contrast, the positively charged small molecules are drawn into the cartilage with uptake and release timescales ranging from hours to days. Using our calibrated computational model, we subsequently explore the effect of small molecule charge and binding constant on the rate of cartilage degradation. The results from this analysis indicate that the small molecules are most effective in inhibiting cartilage degradation if they are either positively charged and/or bind strongly to IL-1α, or both. Furthermore, our results showed that the cartilage structural homeostasis can be restored by the small molecule if administered within six days following initial tissue exposure to IL-1α. We finally extended the scope of the computational model by simulating the competitive inhibition of cartilage degradation by the small molecule. Results from this model show that small molecules are more efficient in inhibiting cartilage degradation by binding directly to IL-1α rather than binding to IL-1α receptors. The results from this study can be used as a template for the design and development of more pharmacologically effective osteoarthritis drugs, and to investigate possible therapeutic options.
Highlights
In this paper, we model both IL-1 driven degradation of cartilage explants and the ability of selected small molecule inhibitors (MW 3 to 10 kDa) to modify this tissue response
This model takes into account: (i) the negative fixed charged on cartilage tissue, (ii) the physiological ionic strength of the support medium/synovial fluid, (iii) the electrical charge on IL-1α and selected drugs and (iv) Donnan partitioning of electrically charged molecules between support medium/synovial fluid and cartilage tissue
We have extended our previous model of IL-1α mediated degradation of bovine calf cartilage explants [1] to include the effects of (i) the negative fixed charge of the cartilage tissue and (ii) the Donnan partitioning of electrically charged species including IL-1α from the synovial fluid/support medium to the cartilage tissue
Summary
We model both IL-1 driven degradation of cartilage explants and the ability of selected small molecule inhibitors (MW 3 to 10 kDa) to modify this tissue response. Our goal is to build a quantitative understanding of IL-1 mediated cartilage degradation in the presence of electrically charged small molecules intended to reduce IL-1 induced cartilage degradation. To this end, we have developed an extended version of our previously experimentally validated computational model used for simulating IL-1α mediated degradation of cartilage tissue [1]. The computational model developed in this study includes all these biochemical interactions, and the interaction of the small molecule with IL-1 or its receptor. Our primary purpose is to develop a computation model for analysing experimental data and investigating hypotheses related to IL-1 driven degradation of cartilage extracellular matrix
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