Network-based cytokine inference implicates Oncostatin M as a driver of an inflammation phenotype in knee
Hirotaka Iijima1,2,3,4,5, Fan Zhang6,7, Fabrisia Ambrosio1,2,3
1Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Charlestown, Massachusetts, USA.
Abstract:
Inflammatory cytokines released by 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 (OSM), as a driver of the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of OSM recapitulated an "inflammatory" 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.
Insights
Aging exacerbates osteoarthritis by altering gene networks. Oncostatin M (OSM) drives aberrant matrix remodeling, offering new therapeutic targets for this inflammatory joint disease.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Rheumatology
Background:
- Inflammatory cytokines from synovium disrupt gene networks post-trauma, contributing to osteoarthritis.
- Understanding aging's role in these processes is crucial for developing new osteoarthritis interventions.
Purpose of the Study:
- To simulate cytokine-mediated communication between synovium and cartilage using network paradigms.
- To identify key molecular drivers of osteoarthritis in aged individuals.
Main Methods:
- Network analysis of injured young and aged murine knee cartilage.
- Cytokine inference and pharmacological manipulation.
- Phenotypic drug discovery approach.
Main Results:
- Aged knees showed unique transcriptomic responses, including aberrant matrix remodeling and accelerated cartilage degradation.
- Oncostatin M (OSM), an IL6 family member, was identified as a key driver of aberrant matrix remodeling.
- OSM activation mimicked inflammatory knee osteoarthritis phenotypes, identifying drug development targets.
Conclusions:
- Aberrant matrix remodeling in aged osteoarthritis is driven by OSM.
- Targeting OSM presents a translational opportunity for treating inflammation-driven osteoarthritis.
- Network-based approaches can uncover novel therapeutic strategies for osteoarthritis.
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