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Thirty six Yucatan minipigs underwent anterior cruciate ligament (ACL) transection and were randomly assigned in equal numbers to no further treatment, reconstruction or ligament repair. Cartilage was harvested at 1 and 4 weeks post\u2010operatively and histology and RNA\u2010sequencing were performed and compared to controls. Microscopic cartilage scores significantly worsened at 1 (<jats:italic>p<\/jats:italic>\u2009=\u20090.028) and 4 weeks (<jats:italic>p<\/jats:italic>\u2009=\u20090.001) post\u2010surgery relative to controls, but did not differ between untreated, reconstruction or repair groups. Gene expression after ACL reconstruction and ACL transection were similar, with only 0.03% (including<jats:italic>SERPINB7<\/jats:italic>and<jats:italic>CR2<\/jats:italic>) and 0.2% of transcripts (including<jats:italic>INHBA<\/jats:italic>) differentially expressed at 1 and 4 weeks respectively.<jats:italic>COL2A1<\/jats:italic>,<jats:italic>COMP<\/jats:italic>,<jats:italic>SPARC<\/jats:italic>,<jats:italic>CHAD<\/jats:italic>, and<jats:italic>EF1ALPHA<\/jats:italic>were the most highly expressed non ribosomal, non mitochondrial genes in the controls and remained abundant after surgery. A total of 1,275 genes were differentially expressed between 1 and 4 weeks post\u2010surgery. With the treatment groups pooled, 682 genes were differentially expressed at both time\u2010points, with the most significant changes observed in<jats:italic>MMP1<\/jats:italic>,<jats:italic>COCH<\/jats:italic>,<jats:italic>POSTN<\/jats:italic>,<jats:italic>CYTL1<\/jats:italic>, and<jats:italic>PTGFR<\/jats:italic>. This study confirmed the development of a microscopic PTOA stage after ACL surgery in the porcine model. Upregulation of multiple proteases (including<jats:italic>MMP1<\/jats:italic>and<jats:italic>ADAMTS4<\/jats:italic>) were found; however, the level of expression remained orders of magnitude below that of extracellular matrix protein\u2010coding genes (including<jats:italic>COL2A1<\/jats:italic>and<jats:italic>ACAN<\/jats:italic>). In summary, genes with established roles in PTOA as well as novel targets for specific intervention were identified. \u00a9 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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