SUMMARY
Inflammatory cytokines released by the synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine-mediated pathological communication between the synovium and cartilage. Cartilage-specific network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees displaying accelerated cartilage degradation. Next, network-based cytokine inference with pharmacological manipulation uncovered IL6 family member, Oncostatin M, as a driver for the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of Oncostatin M recapitulated “inflammation” phenotype of knee osteoarthritis and highlighted high-value targets for drug development and repurposing. These findings offer translational opportunities targeting the inflammation-driven osteoarthritis phenotype.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
To enhance the clinical relevance of our work, these murine findings were compared with the transcriptomic signature of people with KOA and identified that activation of OSM-OSMR axis drives inflammation phenotype of KOA, the major phenotype that represents 16-30% of KOA. These data suggest that targeting the OSM-OSMR axis may represent a promising new therapeutic target in the treatment of inflammation phenotype of KOA. In addition, we propose novel drug candidates that reduce OSM-OSMR signaling and reverse inflammation, offering translational opportunities for the treatment of KOA in the clinic.