Unraveling the complex interplay of sex, endocrinology, and inflammation in post-Injury articular cartilage breakdown through in silico modeling

The onset of degenerative joint diseases such as post-traumatic osteoarthritis (PTOA) are associated with joint injury, biomechanical changes, and synovial biochemical anomalies. Sex and reproductive endocrinology have been emerging as potential risk factors, with epidemiological evidence revealing that female's exhibit higher PTOA risk and poorer outcomes post-injury compared to males. Sex hormones, including estradiol, progesterone, and testosterone, have been shown to regulate inflammatory signaling in immune and synovial cells, yet their collective impact on injury-induced joint inflammation and catabolism is poorly understood. Using an in silico kinetic model, we investigated the effects of sex-specific endocrine states on post-injury mechanisms in the human synovial joint. Our model results reveal that heightened estradiol levels in pre-menopausal females during the peri-ovulatory phase increase interleukin (IL)-1β expression and suppress IL-10 expression within the synovium after a simulated injury. Conversely, elevated testosterone levels in males decrease post-injury IL-1β, tumor necrosis factor alpha (TNF)-α, and stromelysin (MMP)-3 expression while increasing IL-10 production compared to females. Gaining insight into the effects of sex hormones on injury-induced inflammation and cartilage degradation provides a basis for designing future experimental and clinical studies to explore their effects on the synovial system, with a particular focus on the female sex.