Computational Translation of Mouse Models of Osteoarthritis Predicts Human Disease.

Objective: Translation of biological insights from preclinical studies to human disease is a pressing challenge in biomedical research, including in osteoarthritis. Translatable Components Regression (TransComp-R) is a computational framework that has previously been used to synthesize preclinical and human OA data to identify biological pathways predictive of human disease conditions. We aimed to evaluate the translatability of two common murine models of post-traumatic osteoarthritis - surgical destabilization of the medial meniscus (DMM) and noninvasive anterior cruciate ligament rupture (ACLR) - to transcriptomics cartilage data from human OA outcomes.

Design: Transcriptomics cartilage data of DMM and ACLR mouse and human data was acquired from Gene Expression Omnibus. TransComp-R was used to project human OA data into a mouse model (DMM or ACLR) principal component analysis space. The principal components (PCs) were regressed against human OA conditions using increasing complexity of linear regression models incorporating human demographic covariates of OA, sex, and age. Biological pathways of the mouse PCs that significantly stratified human OA and control groups were then interpreted using Gene Set Enrichment Analysis.

Results: From the TransComp-R model, we identified different enriched biological pathways across DMM and ACLR models. While PCs among the DMM models revealed pathways associated with cell signaling and metabolism, ACLR PCs represented immune function and cellular pathways associated with OA condition. The immune pathways presented in the ACLR further highlighted the potential relevance of the OA pathways observed in human conditions.

Conclusions: The ACLR mouse model more successfully predicted human OA conditions, particularly with the human control groups without a history of joint injury or disease. Cross-species translational approaches support the selection of preclinical models intended for therapeutic discovery and pathway analysis in humans.