Journal
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
Volume -, Issue -, Pages -Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/glab386
Keywords
Articular cartilage; Aging; Meta-analysis; Bioinformatics; AGE-RAGE signaling pathway
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Funding
- Japan Society for the Promotion of Science [R01AG052978]
- NIA [R01AG052978, R01AG066198-01, R01AG061005]
- National Institute of General Medical Sciences of the National Institutes of Health [T32GM008208]
- John and Posy Krehbiel Professorship in Orthopedics
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This study used a combined approach of meta-analysis and multi-omics data analysis to uncover the pathogenic mechanisms of age-related knee osteoarthritis (KOA) in mice. Inflammation, autophagy, and cellular senescence were identified as primary hallmarks of age-related KOA. The Advanced Glycation End-Product (AGE)/Receptor for AGE pathway was found to be the most statistically robust pathway associated with age-related KOA. The molecular profiles of cartilage aging were distinct from those observed in surgically induced post-traumatic OA models, suggesting different mechanisms at play.
Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the majority of clinically-presenting KOA, the bulk of our mechanistic understanding of KOA has been derived using surgically induced post-traumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics data analysis to elucidate pathogenic mechanisms of age-related KOA in mice. Protein-level data were integrated with transcriptomic profiling to reveal inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of cartilage aging were unique from those observed following PTOA, with less than 3% overlap between the two models. At the nexus of the three aging hallmarks, Advanced Glycation End-Product (AGE)/Receptor for AGE emerged as the most statistically robust pathway associated with age-related KOA. This pathway was further supported by analysis of mass spectrometry data. Notably, the change in AGE-RAGE signaling over time was exclusively observed in male mice, suggesting sexual dimorphism in the pathogenesis of age-induced KOA in murine models. Collectively, these findings implicate dysregulation of AGE-RAGE signaling as a sex-dependent driver of age-related KOA.
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