Role of Hormones on Bundle-Specific ACL Function in the Growing Knee Joint

PROJECT SUMMARY Anterior cruciate ligament (ACL) injuries impact more than 250,000 people in the U.S. annually. Sex is a major risk factor for ACL injury during adolescence, but not in childhood or adulthood. To explain the increased injury risk for females, several modifiable and non-modifiable risk factors have been explored. Very few of these studies examine the impact on the ACL tissue itself, which in turn, can impact injury risk or the need for patient-specific treatment. The long-term goal of our work is to explore mechanisms by which sex and skeletal growth impact ACL structure, function, injury risk, and treatment. Our prior work has established sex- and region-specific differences in function and cross-sectional area (CSA) within its anteromedial (AM) and posterolateral (PL) bundles. These differences appear around early adolescence and persist as adolescence progresses. Yet, the mechanism driving such sex-specific tissue adaptations is unclear. Earlier initiation of puberty has been associated with greater cumulative estrogen exposure, which may influence ACL bundle function. Additionally, ACL injury risk varies during the menstrual cycle in humans, but the presence of corresponding changes in ACL bundle size and function is unknown. Additionally, a direct relationship between temporal hormone levels and ACL size and function has not been established. Thus, the objective of this proposal is to determine how sex hormones impact ACL bundle size and function. To accomplish this objective, we will leverage our multi- disciplinary experience to accomplish the following aims. Aim 1 examines effect of puberty onset on long-term ACL bundle size and function. In Aim 1a, we will assess how timing of natural puberty onset influences long- term ACL bundle size and function throughout adolescence. In Aim 1b, we will assess whether early induction of puberty and rise in estrogen further alters ACL bundle size and function throughout adolescence. Aim 2 examines the effect of cyclic hormone levels on short-term ACL bundle size and function. In Aim 2a, we will assess how cyclic sex hormone levels influence ACL bundle size and function throughout the normal estrus cycle. In Aim 2b, we will assess whether stabilization of hormone levels reduces cyclic changes in ACL bundle size and function. If successful, this proposal will establish a clear and direct link between natural changes in sex hormones during adolescence and ACL size or function. Ultimately, the information gained can suggest promising human clinical trials of injury risk reduction and new potential treatment strategies.