Cyclic loading induces anabolic 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 quantitative reverse transcription polymerase chain reaction. 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 an anabolic response to cyclic loading at 4 MPa but turned off remodeling at 8 MPa. These data support the hypothesis that noncontact ACL injury may be a consequence of failed tissue remodeling and inadequate repair of microtrauma resulting from elevated loading. Compared to males, female ACLs failed to increase anabolic gene expression with loading and exhibited higher expression of catabolic genes at all loading levels, which may explain the increased rate of ACL tears in women. Together, these data provide insight into load-induced ACL remodeling and potential causes of tissue rupture.