In silico study of principal sex hormone effects on post-injury synovial inflammatory response

Following an anterior cruciate ligament injury, premenopausal females tend to experience poorer outcomes than males, and sex hormones are thought to contribute to the disparity. Evidence seems to suggest that the sex hormones estrogen, progesterone, and testosterone may regulate the inflammation caused by macrophages, which invade the knee after an injury. While the individual effects of hormones on macrophage inflammation have been studied in vitro, their combined effects on post-injury inflammation in the knee have not been examined, even though both males and females have detectable levels of both estrogen and testosterone. In the present work, we developed an in silico kinetic model of the post-injury inflammatory response in the human knee joint and the hormonal influences that may shape that response. Our results indicate that post-injury, sex hormone concentrations observed in females may lead to a more pro-inflammatory, catabolic environment, while the sex hormone concentrations observed in males may lead to a more anti-inflammatory environment. These findings suggest that the female hormonal milieu may lead to increased catabolism, potentially worsening post-injury damage to the cartilage for females compared to males. The model developed herein may inform future in vitro and in vivo studies that seek to uncover the origins of sex differences in outcomes and may ultimately serve as a starting point for developing targeted therapies to prevent or reduce the cartilage damage that results from post-injury inflammation, particularly for females.