Presence of meniscus tear alters gene expression profile of anterior cruciate ligament tears

Anterior cruciate ligament (ACL) tears occur in isolation or in tandem with other intra-articular injuries such as meniscus tears. The impact of injury pattern on the molecular biology of the injured ACL is unknown. Here, we tested the hypothesis that the biological response of the ACL to injury varies based on the presence or absence of concomitant meniscus tear. We performed RNA-seq on 28 ACL tears remnants (12 isolated, 16 combined). In total, 16,654 transcripts were differentially expressed between isolated and combined injury groups at false discovery rate of 0.05. Due to the large number of differentially expressed transcripts, we undertook an Ensembl approach to discover features that acted as hub genes that did not necessarily have large fold changes or high statistical significance, but instead had high biological significance. Our data revealed a negatively correlated module containing 5,960 transcripts (down-regulated in combined injury) and a positively correlated module containing 2,260 transcripts (up-regulated in combined injury). TNS1, MEF2D, NOTCH3, SOGA1, and MLXIP were highly-connected hub genes in the negatively correlated module and SCN2A, CSMD3, LRC44, USH2A, and LRP1B were critical hub genes in the positively correlated module. Transcripts in the negatively correlated module were associated with biological adhesion, actin-filament organization, cell junction assembly, and cell matrix adhesion. The positively correlated module transcripts were enriched for neuron migration and exocytosis regulation. These findings indicate genes and pathways reflective of healing deficiency and gain of neurogenic signaling in combined ACL and meniscus tears, suggesting their diminished repair potential. The biological response of ACL to injury could have implications for healing potential of the ligament and the long term health of the knee. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2612-2621, 2018.