Network-based cytokine inference implicates Oncostatin M as a driver for inflammation phenotype of knee osteoarthritis

Abstract

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 functional network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees. This finding was concomitant with accelerated cartilage degradation, as identified through meta-analysis of histological assessments. Next, cytokine inference with network propagation on the cartilage network uncovered IL6 family member, Oncostatin M (OSM), as a driver for osteoarthritis. Pharmacological manipulations confirmed that the aberrant matrix remodeling is attributed, at least partly, to downstream signals of OSM, but not IL6. These analyses implicate OSM as a promising therapeutic target to ameliorate osteoarthritis in aging through improved synovium-cartilage communication.