Systems Based Study of the Therapeutic Potential of Small Charged Molecules for the Inhibition of IL-1 Mediated Cartilage Degradation

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.

A novel mechanobiological model can predict how physiologically relevant dynamic loading causes proteoglycan loss in mechanically injured articular cartilage

“…Also, collagen damage progression was not taken into account, because we assumed that the damage in the ground substance and the subsequent FCD loss appear before the disorganization of the collagen network, which has been observed previously, especially at a relatively short follow-up period 21 . Future efforts will be focused on combining the adaptation of the collagen content and fibril orientation 23 , 72 as well as inflammatory responses 5 , 73 with the studied degeneration mechanisms after a traumatic joint injury. For those, more experimental data are required.…”

Mechanobiological model for simulation of injured cartilage degradation via pro-inflammatory cytokines and mechanical stimulus

“…Another drawback of the biochemical model is the exclusion of electric charge-based partitioning (Gibbs-Donnan effect) of IL-1 at the cartilage-medium interface. In fact, an updated version of a cytokine diffusion model [9] included the Nernst-Planck equations which would account for the electric charges of IL-1 (valency of -1 [9]) and Donnan partitioning. We are aware that the charge of cytokines may play a role in cytokine diffusion, but this was beyond the scope of the present study.…”

“…Two major mechanisms have been suggested to play a role in PTOA progression. The first mechanism involves joint inflammation [3,6,7] and the resulting diffusion of pro-inflammatory cytokines from the synovial fluid into cartilage [8][9][10][11], leading to proteolysis of cartilage matrix. The second mechanism involves biomechanical factors [12] including induction of chondral defects and aberrant loading characteristics in the knee joint milieu [13][14][15], leading to elevated shear strains near chondral lesions [16][17][18].…”

“…Furthermore, subject-specific numerical models can be helpful in optimization of personalized intervention strategies, rehabilitation procedures, and surgeries. They could also be salutary in development of immunomodulating therapies [22,23] and disease-modifying osteoarthritis drugs [9,24,25]. When validated with experimental data, mechanobiological models can provide key quantitative and qualitative insights into biochemical and biomechanical adaptive processes in cartilage.…”

“…However, tissue inhibitors of metalloproteinases (TIMPs) can slow these catabolic processes by ADAMTS (specifically, TIMP-3 inhibits ADAMTS-4,5 [38]) and MMPs [39]. To predict the experimentally observed cartilage matrix loss [40], Kar and coworkers [9,10] developed a numerical model including the diffusion of IL-1 into cartilage and the subsequent degeneration of tissue aggrecan (the main PG in articular cartilage) and collagen. Other in silico studies [22,26,41] have also sought to cast new light on inflammation and complex biochemically-induced degradation mechanisms of cartilage.…”