Cyclic Loading Induces Anabolic and Catabolic Gene Expression in ACLs in a Load-Dependent and Sex-Specific Manner

Anterior cruciate ligament (ACL) injuries are historically thought to be a result of a single acute overload or traumatic event. However, recent studies suggest that ACL failure may be a consequence of fatigue damage. Additionally, the remodeling response of ACLs to fatigue loading is unknown. Therefore, the objective of this study was to investigate the remodeling response of ACLs to cyclic loading. Furthermore, given that women have an increased rate of ACL rupture, we investigated whether this remodeling response is sex specific. ACLs were harvested from male and female New Zealand white rabbits and cyclically loaded in a tensile bioreactor mimicking the full range of physiological loading (2, 4, and 8 MPa). Expression of markers for anabolic and catabolic tissue remodeling, as well as inflammatory cytokines, was quantified using RT-qPCR. We found that the expression of markers for tissue remodeling of the ACL is dependent on the magnitude of loading and is sex specific. Male ACLs activated a tissue remodeling response to cyclic loading below 4 MPa loads but turned off remodeling at 8 MPa. These data support the hypothesis that noncontact ACL injury is a consequence of failed tissue remodeling and inadequate repair of microtrauma resulting from fatigue loading. Conversely, female ACLs downregulate genes responsible for tissue remodeling in response to cyclic loading at all magnitudes, which may explain the increased rate of ACL tears in women. Together, these data provide insight into the remodeling response of ACLs in vivo and potentially offer novel approaches for preventing ACL rupture.